CN116867488A - Composition for treating dry age-related macular degeneration (AMD) - Google Patents

Composition for treating dry age-related macular degeneration (AMD) Download PDF

Info

Publication number
CN116867488A
CN116867488A CN202180091728.8A CN202180091728A CN116867488A CN 116867488 A CN116867488 A CN 116867488A CN 202180091728 A CN202180091728 A CN 202180091728A CN 116867488 A CN116867488 A CN 116867488A
Authority
CN
China
Prior art keywords
group
alkyl
compound
pharmaceutically acceptable
compounds
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202180091728.8A
Other languages
Chinese (zh)
Inventor
A·卡贾诺
S·卡塔拉诺
M·哈姆比
N·伊佐
G·鲁克
G·里什顿
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Cognition Therapeutics Inc
Original Assignee
Cognition Therapeutics Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Cognition Therapeutics Inc filed Critical Cognition Therapeutics Inc
Publication of CN116867488A publication Critical patent/CN116867488A/en
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/453—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Ophthalmology & Optometry (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The present disclosure relates to methods of treating dry age-related macular degeneration (dry AMD), the methods comprising administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutical composition according to any of the embodiments described herein.

Description

Composition for treating dry age-related macular degeneration (AMD)
Cross Reference to Related Applications
The present application claims priority from U.S. provisional application No. 63/124,695, filed on 11/12/2020, which is incorporated herein by reference.
SUMMARY
The present disclosure provides methods of treating dry age-related macular degeneration (dry AMD) and other retinal diseases, comprising administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutical composition according to any of the embodiments described herein.
Some embodiments describe a method of treating dry age-related macular degeneration (dry AMD), the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound selected from the group consisting of:
a: the compound of the formula I is a compound of formula I,
or a pharmaceutically acceptable salt thereof:
wherein:
R 1 and R is 2 Each of which is independently selected from H, C 1 -C 6 Alkyl, or CH 2 OR'; wherein if R is 1 And R is 2 R 'is present in each R' is independently H or C 1 -C 6 An alkyl group;
R 3 、R 4 、R 5 and R 6 Independently selected from the group consisting of: H. c (C) 1 -C 6 Alkyl, OH, OCH 3 、OCH(CH 3 ) 2 、OCH 2 CH(CH 3 ) 2 、OC(CH 3 ) 3 、O(C 1 -C 6 Alkyl group, OCF 3 、OCH 2 CH 2 OH、O(C 1 -C 6 Alkyl) OH, O (C) 1 -C 6 Haloalkyl), F, cl, br, I, CF 3 、CN、NO 2 、NH 2 、C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Alkoxy C 1 -C 6 Alkyl, aryl, heteroaryl, C 3 -C 7 Cycloalkyl, heterocycloalkyl, alkylaryl, CO 2 R’、C(O)R’、NH(C 1 -C 4 Alkyl), N (C) 1 -C 4 Alkyl group 2 、NH(C 3 -C 7 Cycloalkyl), NHC (O) (C 1 -C 4 Alkyl), CONR' 2 、NC(O)R'、NS(O) n R'、S(O) n NR' 2 、S(O) n R'、C(O)O(C 1 -C 4 Alkyl), OC (O) N (R') 2 、C(O)(C 1 -C 4 Alkyl), and C (O) NH (C) 1 -C 4 An alkyl group); wherein if R is 3 、R 4 、R 5 And R 6 Wherein R 'is present, each R' is independently selected from the group consisting of: H. CH (CH) 3 、CH 2 CH 3 、C 3 -C 6 Alkyl, C 1 -C 6 Haloalkyl, or optionally substituted aryl, alkylaryl, piperazin-1-yl, piperidin-1-yl, morpholinyl, heterocycloalkyl, heteroaryl, C 1 -C 6 Alkoxy, NH (C) 1 -C 4 Alkyl), and N (C) 1 -C 4 Alkyl group 2 Wherein the optionally substituted group is selected from C 1 -C 6 Alkyl or C 2 -C 7 An acyl group;
or R is 3 And R is 4 Forms, together with the C atom to which they are attached, a 4-membered, 5-membered, 6-membered, 7-membered or 8-membered cycloalkyl, aryl, heteroaryl or heterocycloalkyl group optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from: OH, amino, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl,or R is 3 And R is 4 Are joined to form-O-C 1 -C 2 methylene-O-groups;
or R is 4 And R is 5 Forms, together with the C atom to which they are attached, a 4-membered, 5-membered, 6-membered, 7-membered or 8-membered cycloalkyl, aryl, heteroaryl or heterocycloalkyl group optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from: OH, amino, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl, or R 4 And R is 5 Are joined to form-O-C 1-2 methylene-O-groups;
R 7 、R 8 、R 9 、R 10 and R 11 Independently selected from the group consisting of: H. c (C) 1 -C 6 Alkyl, OH, OCH 3 、OCH(CH 3 ) 2 、OCH 2 CH(CH 3 ) 2 、OC(CH 3 ) 3 、O(C 1 -C 6 Alkyl group, OCF 3 、OCH 2 CH 2 OH、O(C 1 -C 6 Alkyl) OH, O (C) 1 -C 6 Haloalkyl), O (CO) R', F, cl, br, I, CF 3 、CN、NO 2 、NH 2 、C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Alkoxy C 1 -C 6 Alkyl, aryl, heteroaryl, C 3 -C 7 Cycloalkyl, heterocycloalkyl, alkylaryl, heteroaryl, CO 2 R’、C(O)R’、NH(C 1 -C 4 Alkyl), N (C) 1 -C 4 Alkyl group 2 、NH(C 3 -C 7 Cycloalkyl), NHC (O) (C 1 -C 4 Alkyl), CONR' 2 、NC(O)R'、NS(O) n R'、S(O) n NR' 2 、S(O) n R'、C(O)O(C 1 -C 4 Alkyl), OC (O) N (R') 2 、C(O)(C 1 -C 4 Alkyl), and C (O) NH (C) 1 -C 4 An alkyl group); wherein if R is 7 、R 8 、R 9 、R 10 And R 11 Wherein R 'is present, each R' is independently selected from the group consisting of: H. CH (CH) 3 、CH 2 CH 3 、C 3 -C 6 Alkyl, C 1 -C 6 Haloalkyl, aryl, alkylaryl, piperazin-1-yl, piperidin-1-yl, morpholinyl, heterocycloalkyl, heteroaryl, C 1 -C 6 Alkoxy, NH (C) 1 -C 4 Alkyl), and N (C) 1 -C 4 Alkyl group 2 ；
Or R is 7 And R is 8 Forms, together with the N or C atom to which they are attached, a 4-, 5-, 6-, 7-, or 8-membered cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from: OH, amino, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl, or R 7 And R is 8 Are joined to form-O-C 1-2 methylene-O-groups;
or R is 8 And R is 9 Forms, together with the N or C atom to which they are attached, a 4-, 5-, 6-, 7-, or 8-membered cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from: OH, amino, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl, or R 8 And R is 9 Are joined to form-O-C 1-2 methylene-O-groups;
each n is independently 0, 1, or 2;
with the proviso that R 7 、R 8 、R 9 、R 10 And R 11 Not all H; and is also provided with
With the proviso that the following compounds or pharmaceutically acceptable salts thereof are excluded:
or alternatively
B: compounds of formula IA
Or a pharmaceutically acceptable salt thereof:
wherein:
R a 、R b 、R c 、R d and R is e Independently selected from the group consisting of: H. hydroxy, cl, F, methyl, -OCH 3 、-OC(CH 3 ) 3 、O-CH(CH 3 ) 2 、CF 3 、SO 2 CH 3 And morpholino;
R 1A selected from the group consisting of: hydrogen, alkyl, phenyl, or-ch=c (CH 3 ) 2 The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with
R 2A Is an optionally substituted cyclic amino group.
Some embodiments of the present disclosure are directed to methods of treating dry age-related macular degeneration (AMD), the methods comprising administering to a subject in need thereof a therapeutically effective amount of a compound selected from the group consisting of:
some embodiments describe a method selected from The use of a compound of (c) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of dry age related macular degeneration.
Some embodiments describe a method comprising selecting from the group consisting of Use of a composition of a compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient in the manufacture of a medicament for the treatment of dry age-related macular degeneration.
Some embodiments describe methods of treating dry age related macular degeneration, the methods comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition according to any of the embodiments described herein.
Some embodiments describe the use of a compound according to any of the embodiments described herein in the manufacture of a medicament for the treatment of dry age-related macular degeneration.
Brief description of the drawings
Fig. 1A and 1B depict cell viability of retinal pigment epithelial cells after treatment with sigma-2 receptor modulators (fig. 1A = compound B and compound C; fig. 1B = compound a).
Fig. 2A and 2B depict photoreceptor outer transport after treatment with aβ oligomers in the presence or absence of a sigma 2 receptor modulator (fig. 2a=compound a and compound C; fig. 2b=compound B).
Fig. 3A and 3B depict photoreceptor outer transport after treatment with oxidative stressors (oxidative stressor) in the presence or absence of sigma 2 receptor modulators (fig. 3a=compound a and compound C; fig. 3b=compound B).
FIG. 4 depicts quantification of autophagy-related proteins after oxidative stress by oxidative stressors in the presence or absence of sigma-2 receptor modulators.
Figure 5 depicts quantification of sigma-2 receptor modulator compound a concentration in rat uvea/retina and brain.
Figure 6 depicts quantification of sigma-2 receptor modulator compound a concentration in mouse plasma, brain and retina.
Figure 7 depicts quantification of sigma-2 receptor modulator compound B concentration in mouse plasma, brain and retina.
Fig. 8 depicts quantification of retinal ganglion cell density in an in vivo model of glaucoma in the presence or absence of sigma-2 receptor modulators.
Fig. 9A and 9B depict quantification of electrical activity in retinal ganglion cells in an in vivo model of glaucoma in the presence or absence of sigma-2 receptor modulators.
Detailed Description
The invention is not limited to the particular processes, compositions, or methods described, as these may vary. The terminology used in the description is for the purpose of describing the particular versions or embodiments only, and is not intended to limit the scope of the present invention. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. All publications mentioned herein are incorporated by reference in their entirety. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.
Definition of the definition
Where a range of values is provided, it is intended that each intervening value, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the disclosure. For example, if a range of 1 μm to 8 μm is specified, it is intended that 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, and 7 μm are also explicitly disclosed.
Substituents of the compounds of the present disclosure are disclosed in groups or in ranges at various positions in the specification. It is specifically intended that embodiments of the present disclosure encompass each and every independent subcombination of the members of such groups and ranges. For example, the term "C 1-6 Alkyl "is particularly intended to disclose independently, for example, methyl (C) 1 Alkyl), ethyl (C) 2 Alkyl), propyl (C) 3 Alkyl), butyl (C) 4 Alkyl), pentyl (C) 5 Alkyl), and hexyl (C) 6 Alkyl), e.g. C 1 -C 2 Alkyl, C 1 -C 3 Alkyl, C 1 -C 4 Alkyl, C 2 -C 3 Alkyl, C 2 -C 4 Alkyl, C 3 -C 6 Alkyl, C 4 -C 5 Alkyl, and C 5 -C 6 An alkyl group.
The articles "a" and "an" as used herein mean "one or more" or "at least one" unless otherwise specified. That is, reference to any element of the present invention by the indefinite articles "a" and "an" does not exclude the possibility that more than one element is present.
As used herein, the term "about" means plus or minus 10% of the numerical value of the number it is using. Thus, about 50mL means in the range of 45mL-55 mL.
The "aβ species" or "aβ" shall comprise compositions comprising components comprising soluble amyloid peptide, such as aβ monomers, aβ oligomers, or complexes of aβ peptide (monomeric, dimeric or multimeric) with other soluble peptides or proteins, as well as other soluble aβ assemblies (including any processed products of amyloid precursor protein). Soluble aβ oligomers are known to be neurotoxic. Even aβ1-42 dimers are known to impair synaptic plasticity in hippocampal slices of mice. In one theory known in the art, the natural aβ1-42 monomers are considered neuroprotective and for neurotoxicity, the aβ monomers need to be self-associated into soluble aβ oligomers. However, certain aβ mutant monomers (arctic mutation (E22G)) are reported to be associated with familial alzheimer's disease.
The term "active ingredient" is understood to mean a compound according to any of the embodiments described herein, unless explicitly stated otherwise.
When used in combination with a compound of the present disclosure, "administration" or the like, provides a compound or pharmaceutical composition according to any of the embodiments described herein to a subject in need of treatment. The subject is preferably a mammal, more preferably a human. The invention includes the administration of the pharmaceutical composition of the invention alone or in combination with additional therapeutic agents. When the pharmaceutical composition of the present invention is administered in combination with another therapeutic agent, the pharmaceutical composition of the present invention and the other therapeutic agent may be administered simultaneously or at different times.
The term "agonist" refers to a compound whose presence results in the biological activity of the receptor that is the same as the biological activity caused by the presence of a naturally occurring ligand of the receptor.
As used herein, the term "alkanoyl" or "alkylcarbonyl" is intended to refer to an alkyl group attached to a carbonyl group. Examples of alkanoyl are
As used herein, the term "alkyl" is intended to mean a saturated hydrocarbon group that is straight or branched. Example alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like. The alkyl groups may contain from 1 to about 20, from 2 to about20, from 1 to about 10, from 1 to about 8, from 1 to about 6, from 1 to about 4, or from 1 to about 3 carbon atoms. "C 1 -C 10 Alkyl "or" C 1-10 Alkyl "is intended to include C 1 Alkyl group, C 2 Alkyl group, C 3 Alkyl group, C 4 Alkyl group, C 5 Alkyl group, C 6 Alkyl group, C 7 Alkyl group, C 8 Alkyl group, C 9 Alkyl group, and C 10 An alkyl group. Also, for example, "C 1 -C 6 Alkyl "or" C 1-6 Alkyl "means an alkyl group having 1 to 6 carbon atoms. The term "alkylene" refers to a divalent alkyl linking group. Examples of hydrocarbylene groups are methylene (CH 2 )。
As used herein, "alkenyl" is intended to encompass hydrocarbon chains of either straight or branched configuration, having one or more (preferably one to three) carbon-carbon double bonds that may be present at any stable point along the chain. For example, "C 2 -C 6 Alkenyl "or" C 2-6 Alkenyl "(or alkenylene) is intended to include C 2 Alkenyl group, C 3 Alkenyl group, C 4 Alkenyl group, C 5 Alkenyl group, and C 6 An alkenyl group. Examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, and 4-methyl-3-pentenyl.
The term "alkoxy" or "alkoxy" refers to an-O-alkyl group. "C 1 -C 6 Alkoxy "or" C 1-6 Alkoxy (or alkoxy) is intended to include C 1 Alkoxy groups, C 2 Alkoxy groups, C 3 Alkoxy groups, C 4 Alkoxy groups, C 5 Alkoxy groups, and C 6 An alkoxy group. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and t-butoxy.
The term "alkoxyalkoxy" refers to an alkoxy group attached to an alkoxy group. Examples of alkoxy groups include-O- (CH) 2 ) 2 -OCH 3 。
As used herein, "alkynyl" is intended to encompass hydrocarbon chains of either straight or branched configuration, having one or more (preferably one to three) carbon-carbon triple bonds that may be present at any stable point along the chain. For example, "C 2 -C 6 Alkynyl "is intended to include C 2 Alkynyl radicals, C 3 Alkynyl radicals, C 4 Alkynyl radicals, C 5 Alkynyl groups, and C 6 Alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, and hexynyl).
As used herein, "beta amyloid effect" (e.g., "non-lethal beta amyloid effect" or "aβ oligomer effect") refers to an effect (particularly a non-lethal effect) on cells contacted with an aβ species. For example, it has been found that when neuronal cells are contacted with soluble β -amyloid ("aβ") oligomers, the oligomers bind to a subset of synapses on a subset of neuronal cells in vitro. This binding can be quantified, for example, in an assay that measures binding of aβ oligomers in vitro. Another document describing the role of aβ species is a decrease in the number of synapses that has been reported to be about 18% in human hippocampus (Scheff et al, 2007) and can be quantified (e.g., in the measurement of the number of synapses). As another example, it has been found that when neuronal cells are contacted with beta-amyloid ("aβ") oligomers, membrane transport is regulated and, in turn, alterations in membrane transport occur. Many assays, including but not limited to MTT assays, can be used to visualize such abnormalities. For example, the yellow tetrazolium salt is endocytosed by the cell and the salt is reduced in the endosomal pathway by enzymes located within the vesicle to insoluble purple formazan (formazan). Purple nail->Is of the level of (2)Reflect the number of active metabolizing cells in culture and A->The reduction in amount is considered a measure of cell death or metabolic toxicity in culture. When observing cells contacted with yellow tetrazolium salt by microscopy, purple methyl +_ is first visible in cell-filled intracellular vesicles>Over time, vesicles are excreted and in insoluble A +.>On exposure to an aqueous medium, methof->Needle-like crystals are precipitated on the outer surface of the plasma membrane. Other effects of the aβ species include cognitive decline (e.g., decline in the ability to form new memory and memory loss), which can be measured in vivo assays using animal models. In some embodiments, the aβ effect is selected from aβ oligomer-induced synaptic dysfunction, such as can be seen in vitro assays (e.g., membrane trafficking assays, or synaptic loss assays, or aβ oligomer-mediated activation of the sigma-2 receptor of caspase-3, or aβ -induced neuronal dysfunction, a decrease in aβ -mediated Long Term Potentiation (LTP), or cognitive decline in behavioral assays, or in patients in need thereof.
In some embodiments, a test compound is considered effective for treating cognitive decline or a disease associated with cognitive decline when it can inhibit an effect associated with a soluble aβ oligomer species on a neuronal cell by more than about 10% (preferably more than 15%, and preferably more than 20%) as compared to a negative control. In some embodiments, a test agent is considered effective when it can inhibit the processed product-mediated effect of an amyloid precursor protein by more than about 10% (preferably more than 15%, and preferably more than 20%) as compared to a positive control. While this specification focuses on inhibition of non-lethal effects on aβ species (such as abnormalities in neuronal metabolism and reduced synaptic numbers), these have been shown to be associated with cognitive function and are expected to cause a reduction in downstream measurable symptoms of amyloid pathology over time (as compared to untreated subjects), especially clinical symptoms such as 1) fibrillar or plaque accumulation as measured by amyloid imaging agents (such as fluorbetapir, pittB or any other imaging agent), 2) synaptic loss or cell death as measured by glucose hypometabolism as detected by FDG-PET, 3) changes in protein expression or metabolite levels in brain or body as detected by ELISA imaging or protein/metabolite detection in brain or body obtained from patients, such as by measured aβ42, phosphorylated tau, changes in levels or rates of total tau, or patterns of detectable protein expression changes in ELISA plates, 4) brain vascular abnormalities as measured by the presence of vascular edema or by detectable micro-bleeding and any other imaging technique as well as cognitive symptoms as detectable loss as measured by any other MRI-5 test (e.g. by MRI-Cog, MMSE, CBIC) by any other measurement of cognitive symptoms such as measured by MRI-Cog, MMSE, CBIC or any other measurement instrument.
As used herein, the term "animal" includes, but is not limited to, human and non-human vertebrates (e.g., wild animals, laboratory animals, domestic animals, and farm animals and pets).
The term "antagonist" refers to an entity (e.g., a compound, antibody, or fragment) whose presence results in a reduction in the magnitude of the biological activity of the receptor. In certain embodiments, the presence of an antagonist results in complete inhibition of the biological activity of the receptor. As used herein, the term "sigma-2 receptor antagonist" is used to describe a compound that acts as a "functional antagonist" of a sigma-2 receptor, as it blocks aβ action (e.g., aβ oligomer-induced synaptic dysfunction), as can be seen, for example, in vitro assays (such as membrane trafficking assays, or synaptic loss assays, or aβ oligomer-mediated sigma-2 receptor activation of caspase-3), or behavioral assays, or in patients in need thereof. Functional antagonists may act directly by inhibiting, for example, binding of aβ oligomer to the sigma-2 receptor, or indirectly by interfering with downstream signaling caused by binding of aβ oligomer to the sigma-2 receptor.
As used herein, "aryl" refers to a monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) aromatic hydrocarbon (e.g., phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, etc.). In some embodiments, the aryl group has from 6 to about 20 carbon atoms. In some embodiments, the aryl group has from 5 to about 10 carbon atoms.
As used herein, "arylalkyl" refers to an aryl group attached to an alkyl group. In a preferred embodiment, the alkyl group is C 1-6 An alkyl group.
As used herein, the term "aroyl" or "arylcarbonyl" refers to an aryl group attached to a carbonyl group. Examples of aroyl groups include, but are not limited to, benzoyl.
As used herein, the term "brain permeability" refers to the ability of a drug, antibody or fragment to cross the blood brain barrier. In some embodiments, an animal pharmacokinetic (pK) study (e.g., a mouse pharmacokinetic/blood brain barrier study) can be used to determine or predict brain permeability. In some embodiments, various concentrations of a compound or pharmaceutical composition according to any of the embodiments described herein may be administered, e.g., at 3mg/kg, 10mg/kg, and 30mg/kg, e.g., orally (p.o.), for 5 days, and various pK properties measured, e.g., in an animal model. In some embodiments, dose-related plasma levels and brain levels are determined. In some embodiments, the brain Cmax > 100ng/mL, 300ng/mL, 600ng/mL, 1000ng/mL, 1300ng/mL, 1600ng/mL, or 1900ng/mL. In some embodiments, good brain permeability is defined as a brain/plasma ratio of > 0.1, > 0.3, > 0.5, > 0.7, > 0.8, > 0.9, preferably > 1, and more preferably > 2, > 5, or > 10. In other embodiments, good brain permeability is defined as greater than about 0.1%, 1%, 5%, greater than about 10%, and preferably greater than about 15% of the administered dose spans the BBB after a predetermined period of time. In certain embodiments, the dosage is administered orally (p.o.). In other embodiments, the dose is administered intravenously (i.v.) prior to measuring the pK properties.
As used herein, "cognitive decline" may be any negative change in cognitive function of an animal. For example, cognitive decline includes, but is not limited to, memory loss (e.g., behavioral memory loss), inability to acquire new memory, confusion, impaired judgment, personality changes, disorientation, or any combination thereof. Thus, a compound effective for treating cognitive decline may be effective by: restoring a balance of synaptic plasticity measured by long-term neuronal enhancement (LTP) or long-term neuronal inhibition (LTD) or electrophysiology; inhibition, treatment, and/or alleviation of neurodegeneration; inhibition, treatment, and/or alleviation of amyloidosis in general; inhibition, treatment, alleviation of one or more of amyloid production, amyloid assembly, amyloid aggregation, and amyloid oligomer binding; inhibition, treatment, and/or alleviation of non-lethal effects (such as synaptic loss or dysfunction and abnormal membrane transport) of neuronal cells by one or more of the aβ species; and any combination thereof. In addition, the compounds may also be effective in treating aβ -related neurodegenerative diseases and disorders, including but not limited to dementia, including but not limited to Alzheimer's Disease (AD), including mild alzheimer's disease, down's syndrome, vascular dementia (cerebral amyloid angiopathy and stroke), dementia with lewy bodies (Dementia with Lewy Bodies), HIV dementia, mild Cognitive Impairment (MCI), age-related memory impairment (AAMI), age-related cognitive decline (ARCD), preclinical alzheimer's disease (PCAD), and non-dementia Cognitive Impairment (CIND).
As used herein, the term "contacting" refers to bringing together or combining molecules (or molecules having a higher order structure (such as cells or cell membranes) such that they are within a distance that allows for intermolecular interactions (such as non-covalent interactions between two peptides or one protein and another protein or other molecules (such as small molecules)), in some embodiments, contacting occurs in solution in which the combined or contacted molecules are mixed in a common solvent and allowed to freely associate.
As used herein, the term "cyclic amino" or "cyclic amino group" is a heterocycloalkyl or heteroaryl group containing a nitrogen group, thus allowing bonding through a nitrogen atom. The group may be of the formula
Representation of->Is any heterocyclic or heteroaromatic ring containing from 0 to 3 additional heteroatoms selected from nitrogen, sulfur and oxygen.
As used herein, the term "cycloalkyl" or "cycloalkylcarbonyl" is intended to describe a cycloalkyl group attached to a carbonyl group. Examples of cycloalkyl groups include, but are not limited to
As used herein, "cycloalkyl" refers to a non-aromatic cyclic hydrocarbon (including cyclized alkyl groups, cyclized alkenyl groups, and cyclized alkynyl groups) containing up to 20 ring-forming carbon atoms. Cycloalkyl groups may comprise monocyclic or polycyclic (e.g., having 2,3, or 4 fused rings) ring systems as well as spiro ring systems. The cycloalkyl group may contain from 3 to about 15, from 3 to about 10, from 3 to about 8, from 3 to about 6, from 4 to about 6, from 3 to about 5, or from 5 to about 6 ring forming carbon atoms. The ring-forming carbon atoms of the cycloalkyl group may optionally be substituted with an oxygen bridge (oxo) or a sulfur bridge (sulfofido). Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcaranyl, adamantyl, and the like. Cycloalkyl is also included in the definition of cycloalkyl as having one or more moieties of an aromatic ring fused to the cycloalkyl ring (i.e., having a bond common to cycloalkyl) (e.g., benzo derivatives or thienyl derivatives of cyclopentane, cyclopentene, cyclohexane, etc. (e.g., 2, 3-dihydro-1H-inden-1-yl or 1H-inden-2 (3H) -one-1-yl)). Preferably, "cycloalkyl" refers to a cyclized alkyl group containing up to 20 ring-forming carbon atoms. Examples of cycloalkyl groups preferably include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, and the like.
The term "cycloalkylalkyl" refers to a cycloalkyl group attached to an alkyl group. In a preferred embodiment, the alkyl group is C 1-6 An alkyl group.
The term "drug-like properties" is used herein to describe pharmacokinetic and stability characteristics (including brain permeability, metabolic stability, and/or plasma stability) of a compound upon administration.
As used herein, the term "effective amount" refers to an amount that results in measurable inhibition of at least one symptom or parameter of a particular disorder or pathological process. For example, the amount of a disclosed compound according to any of the embodiments described herein that provides a measurable lower synaptic decrease in the presence of aβ oligomers is considered an effective amount because it decreases the pathological process even if the clinical symptoms of the amyloid pathology are not altered (at least not immediately).
As used herein, "halogen" or "halogen element" includes fluorine, chlorine, bromine, and iodine.
As used herein, "haloalkoxy" means having a specified number of pass-through oxygensHaloalkyl groups as defined herein of bridged carbon atoms. For example, "C 1 -C 6 Haloalkoxy "or" C 1-6 Haloalkoxy "is intended to include C 1 Haloalkoxy groups, C 2 Haloalkoxy groups, C 3 Haloalkoxy groups, C 4 Haloalkoxy groups, C 5 Haloalkoxy group, and C 6 Haloalkoxy groups. Exemplary haloalkoxy groups are OCF 3 . As used herein, "trihalomethoxy" refers to a methoxy group having three halogen substituents. Examples of trihalomethoxy groups include, but are not limited to, OCF 3 、-OCClF 2 、-OCCl 3 Etc.
As used herein, "haloalkyl" is intended to encompass both branched saturated aliphatic hydrocarbon groups and straight saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with one or more halogen elements. Exemplary haloalkyl groups include, but are not limited to, CF 3 、C 2 F 5 、CHF 2 、CCl 3 、CHCl 2 、C 2 Cl 5 、CH 2 CF 3 Etc.
As used herein, a "heteroaryl" group refers to an aromatic heterocycle having up to 20 ring-forming atoms and having at least one heteroatom ring member (ring-forming atom), such as sulfur, oxygen, or nitrogen. In some embodiments, the heteroaryl group has at least one or more heteroatom ring forming atoms, each independently selected from sulfur, oxygen, and nitrogen. Heteroaryl groups include monocyclic and polycyclic ring systems (e.g., having 2, 3, or 4 fused rings). Examples of heteroaryl groups include, but are not limited to, pyridinyl (also known as pyridyl), pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl (also known as pyrrolyl), oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2, 4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, and the like. In some embodiments, heteroaryl groups have from 1 to about 20 carbon atoms, and in further embodiments from about 1 to about 5, from about 1 to about 4, from about 1 to about 3, from about 1 to about 2 carbon atoms as ring forming atoms. In some embodiments, the heteroaryl group contains 3 to about 14, 3 to about 7, or 5 to 6 ring forming atoms. In some embodiments, the heteroaryl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms.
As used herein, the term "heterocycloalkoxy" refers to an-O-heterocycloalkyl group. Examples of heterocycloalkoxy groups are
As used herein, "heterocycloalkyl" or "heterocyclyl" refers to a non-aromatic heterocyclyl group (including cyclized alkyl groups, cyclized alkenyl groups, and cyclized alkynyl groups) having up to 20 ring-forming atoms in which one or more of the ring-forming carbon atoms are replaced by a heteroatom (e.g., an O atom, an N atom, or an S atom). The heterocycloalkyl group can be monocyclic or polycyclic (e.g., both fused and spiro systems). For example, "heterocycloalkyl" groups include morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2, 3-dihydrobenzofuranyl, 1, 3-benzodioxazole, benzo-1, 4-dioxane, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, pyrrolidin-2-one-3-yl, and the like. The ring-forming carbon atoms and heteroatoms of the heterocycloalkyl group can be optionally substituted with oxygen or sulfur bridges. For example, the ring-forming S atom may be substituted with 1 or 2 oxygen bridges (i.e., to form S (O) or S (O) 2 ). For example, the ring-forming C atom may be substituted with an oxygen bridge (i.e., form a carbonyl group). Also included in the definition of heterocycloalkyl are moieties having one or more aromatic rings fused to (i.e., having a bond common to) a non-aromatic heterocycle (e.g., pyridyl, thiophenyl, phthalimidyl, naphthaloyl)Imino-and heterocyclic-benzo derivatives (e.g., indoline, isoindoline, isoindolin-1-one-3-yl, 4,5,6, 7-tetrahydrothieno [2, 3-c)]Pyridin-5-yl, 5, 6-dihydrothieno [2,3-c]Pyridin-7 (4H) -one-5-yl, and 3, 4-dihydroisoquinolin-1 (2H) -one-3 yl group)). The ring-forming carbon atoms and heteroatoms of the heterocycloalkyl group can be optionally substituted with oxygen or sulfur bridges. In some embodiments, the heterocycloalkyl group has from 2 to about 20 carbon atoms or from 3 to about 20 carbon atoms. In some embodiments, the heterocycloalkyl group contains 3 to about 14, 3 to about 7, or 5 to 6 ring forming atoms. In some embodiments, the heterocycloalkyl group has 1 to 4 heteroatoms. In some embodiments, the heterocycloalkyl group contains from 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains from 0 to 2 triple bonds.
In the present application, the term "high affinity" is intended to mean exhibiting a K in the sigma receptor binding assay of less than 600nM, 500nM, 400nM, 300nM, 200nM, less than 150nM, less than 100nM, less than 80nM, less than 60nM, or preferably less than 50nM i Compounds of the value, e.g. relative to [3H]DTG, as disclosed in Weber et al, proc. Natl. Acad. Sci (USA) 83:8784-8788 (1986), which is incorporated herein by reference, which measures the binding affinity of compounds for both sigma-1 and sigma-2 receptor sites. Particularly preferred compounds are relative to [3H ]]-DTG exhibits a K of less than about 150nM, preferably less than 100nM, less than about 60nM, less than about 10nM, or less than about 1nM i Values.
The terms "hydroxyl" and "hydroxyl" are used interchangeably to denote OH groups.
The term "improving" is used to indicate that the present disclosure alters the characteristics and/or physical properties of the tissue to which the present disclosure is provided, applied or applied. The term "ameliorating" may also be used in conjunction with a disease state such that when the disease state is "ameliorated," symptoms or physical features associated with the disease state are reduced, eliminated, delayed, or avoided.
The term "inhibit" encompasses blocking, avoidance of certain results or processes, or restoration of the opposite result or process. In the prophylactic or therapeutic aspect, "inhibiting" comprises protecting against (partially or wholly) or delaying the onset of symptoms, alleviating symptoms, or protecting against, reducing or eliminating a disease, condition, or disorder by administering a compound of the present disclosure.
The term "inhibit trafficking defect" refers to the ability to block soluble aβ oligomer-induced membrane trafficking defects in cells, preferably neuronal cells. Compounds capable of inhibiting transport defects have an EC of < 20. Mu.M, less than 15. Mu.M, less than 10. Mu.M, less than 5. Mu.M, and preferably less than 1. Mu.M in a membrane transport assay 50 And also is capable of maximally inhibiting at least 50%, preferably at least 60%, and more preferably at least 70% of the aβ oligomer action of soluble aβ oligomer-induced membrane transport defects, e.g. as described in example 6.
The term "log P" refers to the partition coefficient of a compound. The partition coefficient is the ratio of the concentrations of the non-ionized compounds in each of the two solution phases (e.g., octanol and water). To measure the partition coefficient of the ionizable solute compound, the pH of the aqueous phase is adjusted so that the predominant form of the compound is not ionized. The logarithm of the ratio of the concentration of the non-ionized solute compound in the solvent is referred to as log P. log P is a measure of lipophilicity. For example, the number of the cells to be processed,
log P octanol/water Log ([ solute ]] Octanol (octanol) Solute/[ solute ]] Non-ionized water )。
As used herein, the term "metabolic stability" refers to the ability of a compound to survive first pass metabolism (intestinal degradation and hepatic degradation or binding of orally administered drugs). This can be assessed, for example, in vitro by exposing the compound to mouse liver microsomes or human liver microsomes. In some embodiments, good metabolic stability refers to t when the compound is exposed to mouse or human liver microsomes 1/2 > 5min, > 10min, > 15 min, > 20 min, and preferably > 30min. In some embodiments, good metabolic stability refers to an intrinsic clearance (Cl) of < 300 μL/min/mg (preferably 200 μL/min/mg or less, and more preferably 100 μL/min/m or less) int )。
The term "n-member" (where n is an integer) generally describes the number of ring-forming atoms in a moiety, where the number of ring-forming atoms is n. For example, pyridine is an example of a 6 membered heteroaryl ring, while thiophene is an example of a 5 membered heteroaryl group.
As used herein, the term "natural ligand" refers to a ligand that is present in a subject that can bind to a protein, receptor, membrane lipid, or other binding partner that replicates in vivo or in vitro. The natural ligand may be of synthetic origin, but also has to be naturally present in the subject without human intervention. For example, the presence of aβ oligomers in human subjects is known. Thus, aβ oligomers found in a subject will be considered as natural ligands. Binding of the aβ oligomer to the binding partner can be replicated in vitro using recombinant or synthetic techniques, but regardless of how the aβ oligomer is prepared or manufactured, the aβ oligomer is still considered to be a natural ligand. Synthetic small molecules that can also bind to the same binding partner are not natural ligands if they are not present in the subject. For example, the compounds described herein are not typically present in a subject, and thus, will not be considered natural ligands.
As used herein, the term "neuronal cell" may be used to refer to a single cell or a population of cells. In some embodiments, the neuronal cell is a primary (primary) neuronal cell. In some embodiments, the neuronal cell is an immortalized or transformed neuronal cell or stem cell. Primary neuronal cells are neuronal cells that are unable to differentiate into other types of neuronal cells (e.g., glial cells). Stem cells are cells that can differentiate into neurons and other types of neuronal cells (e.g., glia). In some embodiments, the assay utilizes a composition comprising at least one neuronal cell without glial cells. In some embodiments, the composition comprises less than about 30%, 25%, 20%, 15%, 10%, 5%, or 1% of glial cells, which are known to internalize and accumulate aβ. The primary neuronal cells may originate from any region of the brain of the animal. In some embodiments, the neuronal cell is a hippocampal cell or a cortical cell. The presence of glial cells may be determined by any method. In some embodiments, glial cells are detected by the presence of GFAP, and neurons can be detected by positive staining with antibodies to MAP 2.
As used herein, the term "optionally substituted" means that substitution is optional and thus encompasses both unsubstituted atoms and moieties and substituted atoms and moieties. "substituted" atom or moiety means that any hydrogen on the indicated atom or moiety can be replaced with a selection from the indicated substituent group, provided that: no more than the normal valence of the specified atom or moiety, and substitution results in a stable compound. For example, if the methyl group (i.e., CH 3 ) Optionally substituted, up to 3 hydrogen atoms on a carbon atom may be replaced with a substituent group. Substituent groups include, but are not limited to, alkanoyl, alkoxy, alkoxyalkyl, (alkoxy) alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, aroyl, cycloalkanoyl, substituted or unsubstituted C 3 -C 10 Cycloalkyl, -OC (O) NCH (CH) 3 ) 2 (N, N-dimethylamino) pyridinyl, (N, N-dimethylamino) sulfonyl, halogen, heterocyclyl, (heterocyclyl) alkoxyalkyl, heterocycloalkyl, hydroxy, hydroxyalkyl, methylpiperidinyl, methylsulfonyl, methylsulfonylphenyl, morpholinylpyridinyl, optionally substituted C 1 -C 10 Alkyl, optionally substituted C 5 -C 10 Aryl, optionally substituted C 3 -C 10 Heteroaryl, perfluoroalkyl, phenyl, piperidinyl, pyrrolidinylpyridinyl, tetrahydropyranyl, CF 3 . For example, a substituted alkyl group means that one or more hydrogen atoms on the alkyl group are replaced with a substituent group selected from, but not limited to, halogen, hydroxy, alkoxy, heterocycloalkoxy, alkoxyalkoxy, C (O) OMe and C (O) OEt. For example, a substituted aryl group means that one or more hydrogen atoms on the aryl group are replaced with a substituent group selected from (but not limited to) -SO 2 Me or phenyl groups. For example, substituted heteroaryl means that one or more hydrogen atoms on the heteroaryl group are replaced with a substituent group selected from (but not limited to) heterocycloalkyl, heteroaryl, N-dimethylaminoamineA base. For example, a substituted heterocycloalkyl group means that one or more hydrogen atoms on the heteroaryl group is replaced with a substituent group selected from (but not limited to) heterocycloalkyl, heteroaryl, N-dimethylamino, hydroxy, alkoxy, alkoxycarbonyl, alkyl, aryl, sulfonyl, dimethylaminosulfonyl, aroyl, cycloalkanoyl, alkanoyl, and-OC (O) NCH (CH) 3 ) 2 . In some cases, two hydrogen atoms on the same carbon, e.g., heterocyclyl or alkyl groups, are replaced with groups to form a spiro compound selected from, but not limited to, e.g.
The term "partial agonist" refers to a compound whose presence results in the biological activity of the receptor (which is of the same type but of a lower magnitude than the biological activity caused by the presence of the naturally occurring ligand of the receptor).
The phrase "pharmaceutically acceptable" refers to molecular entities and compositions that are generally considered safe and nontoxic. In particular, the pharmaceutically acceptable carriers, diluents, or other excipients used in the pharmaceutical compositions of the present disclosure are physiologically tolerable, compatible with the other ingredients, and generally do not produce allergic or similar untoward reactions (e.g., gastric discomfort, dizziness, etc.) when administered to a patient. Preferably, as used herein, the term "pharmaceutically acceptable" means approved by a federal regulatory agency or a state government or listed in the U.S. pharmacopeia or other generally recognized pharmacopeia for use in animals, and more preferably in humans.
As used herein, the phrase "pharmaceutically acceptable salt(s)" includes those salts of the compounds of the present disclosure that are safe and effective for use in mammals and have the desired biological activity. Pharmaceutically acceptable salts include salts of acidic or basic groups present in the compounds of the present disclosure or in compounds identified according to the methods of the present disclosure. Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate (glucaronate), gluconate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1' -methylene-bis- (2-hydroxy-3-naphthoate)). Certain compounds of the present disclosure may form pharmaceutically acceptable salts with various amino acids. Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, iron, and diethanolamine salts. Pharmaceutically acceptable base addition salts are also formed with amines, such as organic amines. Examples of suitable amines are N, N' -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine.
As used herein, the term "pharmaceutically acceptable carrier" encompasses any of the standard pharmaceutical carriers (e.g., phosphate buffered saline solution, water, emulsions (e.g., oil/water emulsions or water/oil emulsions), and various types of wetting agents). The term also encompasses any of the agents approved by a regulatory agency of the federal government or listed in the U.S. pharmacopeia for use in animals, including humans.
The terms "selectivity" and "selective" refer to the binding affinity (K) of a compound for a sigma receptor (e.g., sigma-2 receptor) as compared to a non-sigma receptor i ) Is a difference in (a) between the two. The compounds have high selectivity for sigma receptors in synaptic neurons. The Ki of the sigma-2 receptor or the Ki of both the sigma-2 receptor and the sigma-1 receptor are compared to the Ki of the non-sigma receptor. In some embodiments, the compound is a selective sigma-2 receptor antagonist, or sigma-1 receptor ligand, and is prepared, for example, by comparing the binding dissociation constants K at the different receptors i Value, or IC 50 The value, or binding constant, estimated for binding to sigma receptorHas at least 10-fold, 20-fold, 30-fold, 50-fold, 70-fold, 100-fold, or 500-fold or more affinity than non-sigma receptor binding. Any known assay can be used to evaluate K at different receptors i Value or IC 50 Values (e.g., by monitoring competitive displacement of radiolabeled compounds having known dissociation constants from the receptor, e.g., by methods of Cheng and Prusoff (1973) (biochem. Pharmacol.22, 3099-3108) or methods specifically provided herein).
As used herein, the term "plasma stability" refers to the degradation of a compound in plasma, for example, by enzymes (e.g., hydrolases and esterases). Any of a variety of in vitro assays may be employed. The test compounds were incubated in plasma for multiple periods of time. The percentage of parent compound (analyte) remaining at each time point reflects plasma stability. Poor stability characteristics may tend to have low bioavailability. Good plasma stability can be defined as: more than 50% of the analyte remains after 30min, more than 50% of the analyte remains after 45 min, and preferably more than 50% of the analyte remains after 60 min.
"sigma-2 ligand" refers to a compound that binds to a sigma-2 receptor and includes competitors of agonists, antagonists, partial agonists, inverse agonists, and simply other ligands for that receptor or protein.
The term "sigma-2 receptor antagonist compound" refers to a compound that binds sigma-2 receptor in a measurable amount and acts as a functional antagonist against aβ -acting oligomer-induced synaptic dysfunction caused by sigma-2 receptor binding.
As used herein, the terms "subject," "individual," or "patient" are used interchangeably and are intended to include humans and non-human animals. Although mammals (e.g., non-human primates, sheep, dogs, cats, cattle, and horses) are preferred, non-human animals include all vertebrates (e.g., mammals and non-mammals such as non-human primates, sheep, dogs, cats, cattle, horses, chickens, amphibians, and reptiles). Preferred subjects comprise human patients. The methods are particularly suitable for treating human patients suffering from the diseases or disorders described herein.
A "test compound" is a compound according to any embodiment described herein that is tested in any test. The test includes any in vivo or in vitro test, computer model or computer simulation, virtual drug test, stem cell test method and genetic test method, non-invasive imaging technique, and the like.
As used herein, the term "therapeutic agent" refers to an agent for treating, combating, ameliorating, protecting against or ameliorating an undesired condition or disease in a subject.
A "therapeutically effective amount" of a compound, pharmaceutically acceptable salt of a compound, or pharmaceutical composition according to any of the embodiments described herein is an amount sufficient to produce a selected effect on at least one symptom or parameter of a particular disease or disorder. The therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., the subject gives an indication of the effect or feels the effect, or the physician observes a change). A therapeutically effective amount of a compound according to any of the embodiments described herein may generally range from 0.01mg/kg body weight to about 500mg/kg body weight, from about 0.01mg/kg body weight to about 250mg/kg body weight, from about 0.01mg/kg body weight to about 25mg/kg body weight, from about 0.05mg/kg body weight to about 20mg/kg body weight, from about 0.1mg/kg body weight to about 400mg/kg body weight, from about 0.1mg/kg body weight to about 200mg/kg body weight, from about 0.1mg/kg body weight to about 25mg/kg body weight, from about 0.1mg/kg body weight to about 10mg/kg body weight, from about 0.2mg/kg body weight to about 5mg/kg body weight, from about 1mg/kg body weight to about 300mg/kg body weight, from about 10mg/kg body weight to about 100mg/kg body weight. The effects contemplated herein suitably include both medical treatment and/or prophylactic treatment. The particular dosage of a compound administered according to the present disclosure to achieve a therapeutic and/or prophylactic effect is determined according to the particular circumstances associated with the case, and includes, for example, the compound administered, the route of administration, co-administration of other active ingredients, the condition being treated, the activity of the particular compound employed, the particular composition employed, the age, weight, general health, sex, and diet of the patient; the time of administration, the route of administration, the rate of excretion of the particular compound being employed, and the duration of the treatment. The therapeutically effective amount administered is determined by the physician in light of the foregoing considerations and the use of sound medical judgment. A therapeutically effective amount of a compound according to any of the embodiments described herein is generally an amount sufficient to achieve an effective systemic or local tissue concentration when administered in a physiologically tolerable excipient composition. The amount of the daily total dose of a compound according to any of the embodiments described herein administered to a human or other animal in a single dose or divided dose may be, for example, from about 0.01mg/kg body weight/day to about 500mg/kg body weight/day, about 0.01mg/kg body weight/day to about 250mg/kg body weight/day, about 0.01mg/kg body weight/day to about 25mg/kg body weight/day, about 0.05mg/kg body weight/day to about 20mg/kg body weight/day, about 0.1mg/kg body weight/day to about 400mg/kg body weight/day, about 0.1mg/kg body weight/day to about 200mg/kg body weight/day, about 0.1mg/kg body weight/day to about 25mg/kg body weight/day, about 0.1mg/kg body weight/day to about 10mg/kg body weight/day, about 0.2mg/kg body weight/day to about 5mg/kg body weight/day, about 1mg/kg body weight/day to about 300mg/kg body weight/day, about 10mg/kg body weight/day to about 100 mg/day. A single dose of a pharmaceutical composition of any of the embodiments described herein may contain such amount or a factor of such amount to make up a daily dose. For example, compounds according to any of the embodiments described herein may be administered according to a regimen of 1 to 4 times per day (e.g., once per day, twice per day, three times per day, or four times per day). In some embodiments, a therapeutically effective amount of a compound according to any of the embodiments disclosed herein can be in the range of about 0.01 mg/kg/day to about 25 mg/kg/day. In some embodiments of the present invention, in some embodiments, the therapeutically effective amount is about 0.01mg/kg body weight, about 0.1mg/kg body weight, about 0.2mg/kg body weight, about 0.3mg/kg body weight, about 0.4mg/kg body weight, about 0.5mg/kg body weight, about 0.60mg/kg body weight, about 0.70mg/kg body weight, about 0.80mg/kg body weight, about 0.90mg/kg body weight, about 1mg/kg body weight, about 2.5mg/kg body weight, about 5mg/kg body weight, about 7.5mg/kg body weight, about 10mg/kg body weight, about 12.5mg/kg body weight, about 15mg/kg body weight, about 17.5mg/kg body weight, about 20mg/kg body weight, about 22.5mg/kg body weight, about 25mg/kg body weight, a lower limit of about 25mg/kg body weight, and 25mg/kg body weight about 22.5mg/kg body weight, about 20mg/kg body weight, about 17.5mg/kg body weight, about 15mg/kg body weight, about 12.5mg/kg body weight, about 10mg/kg body weight, about 7.5mg/kg body weight, about 5mg/kg body weight, about 2.5mg/kg body weight, about 1mg/kg body weight, about 0.9mg/kg body weight, about 0.8mg/kg body weight, about 0.7mg/kg body weight, about 0.6mg/kg body weight, about 0.5mg/kg body weight, about 0.4mg/kg body weight, about 0.3mg/kg body weight, about 0.2mg/kg body weight, about 0.1mg/kg body weight, and an upper limit of about 0.01mg/kg body weight. In some embodiments, the therapeutically effective amount is from about 0.1 mg/kg/day to about 10 mg/kg/day; in some embodiments, the therapeutically effective amount is about 0.2 mg/kg/day and about 5 mg/kg/day. In some embodiments, a treatment regimen according to the present disclosure includes administration to a patient in need of such treatment in a single dose or multiple doses per day, the administration will typically comprise from about 1mg to about 5000mg, about 10mg to about 2000mg, about 10mg to about 200mg, about 20 to about 1000mg, about 20 to about 500mg, about 20 to about 400mg, about 40 to about 800mg, about 50mg to about 500mg, about 80 to about 1600mg, and about 50mg of a compound according to any of the embodiments described herein, or a pharmaceutically acceptable salt of a compound according to any of the embodiments described herein. In some embodiments, the therapeutically effective amount is a total daily dose of 50mg to 500 mg. In some embodiments of the present invention, in some embodiments, the daily dose is about 50mg, about 55mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, about 105mg, about 110mg, about 115mg, about 120mg, about 125mg, about 130mg, about 135mg, about 140mg, about 145mg, about 150mg, about 155mg, about 160mg, about 165mg, about 170mg, about 175mg, about 180mg, about 185mg, about 190mg, about 195mg, about 200mg, about 205mg, about 210mg, about 215mg, about 220mg, about 225mg, about 230mg, about 235mg, about 240mg, about 245mg, about 250mg, about 255mg, about about 260mg, about 265mg, about 270mg, about 275mg, about 280mg, about 285mg, about 290mg, about 295mg, 300mg, about 305mg, about 310mg, about 315mg, about 320mg, about 325mg, about 330mg, about 335mg, about 340mg, about 345mg, about 350mg, about 355mg, about 360mg, about 365mg, about 370mg, about 375mg, about 380mg, about 385mg, about 390mg, about 395, about 400mg, about 405mg, about 410mg, about 415mg, about 420mg, about 425mg, about 430mg, about 435mg, about 440mg, about 445mg, about 450mg, about 455mg, about 460mg, about 465mg about 260mg, about 265mg, about 270mg, about 275mg, about 280mg, about 285mg, about 290mg, about 295mg, 300mg, about 305mg, about 310mg, about 315mg, about 320mg, about 325mg, about 330mg, about 335mg, about 340mg, about 345mg, about 350mg, about 355mg, about 360mg, about about 365mg, about 370mg, about 375mg, about 380mg, about 385mg, about 390mg, about 395, about 400mg, about 405mg, about 410mg, about 415mg, about 420mg, about 425mg, about 430mg, about 435mg, about 440mg, about 445mg, about 450mg, about 455mg, about 460mg, about 465mg, about, about 120mg, about 115mg, about 110mg, about 105mg, about 100mg, about 95mg, about 90mg, about 85mg, about 80mg, about 75mg, about 70mg, about 65mg, about 60mg, about 55mg, and between the upper limits of about 50mg of a compound according to any embodiment herein. In some embodiments, the total daily dose is about 50mg to 150mg. In some embodiments, the total daily dose is about 50mg to 250mg. In some embodiments, the total daily dose is about 50mg to 350mg. In some embodiments, the total daily dose is about 50mg to 450mg. In some embodiments, the total daily dose is about 50mg. It will be understood that the pharmaceutical formulations of the present disclosure need not necessarily contain the entire amount of the compound that is effective in treating a disorder, as such effective amounts can be achieved by administering multiple divided doses of such pharmaceutical formulations. The compounds may be administered according to a regimen of 1 to 4 times per day (e.g., once per day, twice per day, three times per day, or four times per day).
The term "therapeutic phenotype" is used to describe the pattern of activity of a compound in an in vitro assay that predicts the efficacy of a behavior. If (1) binds selectively to sigma-2 receptor with high affinity and (2) compound (i) acting as a functional antagonist against aβ oligomer-induced action in neurons blocks or reduces aβ -induced membrane transport defects; (ii) Blocking or reducing aβ -induced synaptic loss, and (iii) does not affect trafficking or synaptic number in the absence of aβ oligomers, it is considered to have a "therapeutic phenotype". This pattern of activity in vitro assays is termed a "therapeutic phenotype" and can predict behavioral efficacy.
The term "treatment profile (therapeutic profile)" is used to describe a compound that satisfies the treatment phenotype and also has good brain penetration (ability to cross the blood brain barrier), good plasma stability, and good metabolic stability.
The term "tissue" refers to any collection of similarly specialized cells that collectively perform a particular function.
As used herein, the terms "treatment", "treatment" or "treatment" refer to both therapeutic and prophylactic (prophoric) measures, wherein the aim is to protect against (partially or fully) or slow (e.g., reduce or delay) the onset of an undesired physiological condition, disorder or disease, or to obtain a beneficial or desired clinical outcome (e.g., partial or full recovery, or to inhibit a decrease in a parameter, value, function or outcome that has become abnormal or will become abnormal). For the purposes of this disclosure, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; a decrease in the extent or activity or rate of progression of a condition, disorder or disease; stabilization (i.e., not worsening) of a condition, disorder or disease state; delay in onset or slowing of progression of a condition, disorder or disease; improvement of a condition, disorder or disease state; and relief (whether partial or complete) (whether or not translated into immediate relief of actual clinical symptoms, or exacerbation or amelioration of a condition, disorder or disease). Treatment seeks to elicit a clinically significant response without undue levels of side effects. Treatment also includes prolonging survival compared to the expected survival if not treated.
Human beta-amyloid and sigma-2 antagonists
Dysfunction of Retinal Pigment Epithelium (RPE) cells plays a key role in the development of Geographic Atrophy (GA) dry age-related macular degeneration (AMD). There is strong evidence for the beta-amyloid (aβ) protein associated with alzheimer's disease. Smaller soluble aβ oligomers interfere with some signaling pathways.
One subset of sigma-2 receptor binding sites/signaling pathways are involved in aβ oligomer signaling in alzheimer's disease, and knockout of sigma-2 receptors protects retinal pigment epithelial cells (RPEs) from oxidative stress-induced cell death. Sigma-receptors are involved in a number of signaling pathways (e.g., heme binding, cytochrome P450 metabolism, cholesterol synthesis, progesterone signaling, apoptosis, and membrane trafficking). Dysfunction of Retinal Pigment Epithelium (RPE) cells plays a key role in the development of Geographic Atrophy (GA) dry Age Macular Degeneration (AMD), and there is strong evidence that β -amyloid (aβ) proteins associated with alzheimer's disease are involved in this process.
With aging population, vision loss is becoming a major public health problem. The U.S. blind foundation reports that blindness or low vision affects people in the united states who are 3220 tens of thousands of americans 18 years old and older. The most common eye diseases in americans aged 40 and older are age-related macular degeneration, glaucoma, cataracts, and diabetic retinopathy. The causes of these diseases are diverse and include damage, exposure to 15 toxins, potential health conditions (e.g., diabetes, arteriosclerosis), and genetic factors (e.g., aqueous humor excess). These diseases are not cured except for cataracts (the lens can be resected and replaced), and vision loss is often permanent
There is a need for protective compounds that inhibit, reduce or otherwise treat vision impairment or progression. These protective compounds are useful in terms of damage caused by impact or toxic chemicals, including counteracting toxic side effects associated with certain chemotherapy regimens, or improving the quality of life of people experiencing progressive vision impairment.
While not being bound by theory, it is proposed that sigma-2 receptors are receptors for aβ oligomers in retinal pigment epithelial cells (RPEs) and Retinal Ganglion Cells (RGCs) of the eye. Various receptors have been proposed in the literature for soluble aβ oligomers, including prion proteins, insulin receptors, β adrenergic receptors and RAGE (receptor for glycosylated end products). Lauren, J.et al,2009, nature,457 (7233): 1128-1132; townsend, M.et al, J.biol. Chem.2007,282:33305-33312; stuchler, E.et al,2008, J.Neurosci.28 (20): 5149-5158. Many researchers do believe that aβ oligomers can bind to more than one receptor protein. Without being bound by theory, the inventors postulate additional receptors for aβ oligomers located in the eye.
Without being bound by theory, aβ oligomers are sigma receptor agonists that bind to the sigma protein complex and cause abnormal trafficking and cellular damage. It is demonstrated herein that compounds described herein that antagonize this interaction and/or sigma receptor function in RPE and/or RGC will compete with or otherwise interfere with aβ oligomers to prevent further cell damage and cell death. Such compounds are considered to be functional sigma-2 receptor antagonists for the treatment of eye-related neurodegenerative diseases (e.g., age-related macular degeneration).
In some embodiments, a compound according to any of the embodiments described herein may be used as a functional antagonist in an RPE or RGC for: inhibit soluble aβ oligomer-induced cell damage or cell death, and inhibit soluble aβ oligomer-induced defects in membrane trafficking assays and cell health assays.
In some embodiments, a compound according to any of the embodiments described herein that is used as a functional antagonist of certain in vitro assay criteria detailed herein will exhibit or be predicted to have behavioral efficacy in one or more relevant in vitro assays or animal behavioral models.
According to the in vitro assay platform, compounds of any of the embodiments described herein can bind to sigma-2 receptors with high affinity; the role induced by aβ oligomers in RPE and RGC serves as a functional antagonist; inhibit aβ oligomer-induced cell damage or death in RPE or RGC; and does not affect membrane trafficking or cell health in the absence of aβ oligomers. This pattern of activity in an in vitro assay is referred to as the "therapeutic phenotype". The ability of a compound according to any of the embodiments described herein to block aβ oligomer effects in RPE and RGC without affecting normal function in the absence of aβ oligomer meets the criteria for a therapeutic phenotype. Compounds of any of the embodiments described herein having a therapeutic phenotype may block aβ oligomer-induced RPE and RGC cell damage or death.
In some embodiments, compounds according to any of the embodiments described herein exhibit sigma-2 antagonist activity, high affinity for sigma-2 receptors, and the ability to block soluble aβ oligomer binding or aβ oligomer-induced RPE and RGC cell damage or death.
In some embodiments, a compound according to any of the embodiments described herein blocks binding between soluble aβ oligomer and sigma-2 receptor.
In some embodiments, a compound according to any of the embodiments described herein exhibits high affinity for sigma-2 receptors.
Method of application
Various embodiments are directed to methods of treating an ocular-related neurodegenerative disease, the methods comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein.
Some embodiments are directed to a method of treating a subject selected from the group consisting of Use of a compound or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of dry age-related macular degeneration as described herein.
Some embodiments are directed to methods comprising a step of selecting Or a pharmaceutically acceptable compound thereofUse of a composition of a salt, and a pharmaceutically acceptable excipient, in the manufacture of a medicament for the treatment of dry age-related macular degeneration as described herein. / >
In some embodiments, the ocular-related neurodegenerative disease is selected from the group consisting of: glaucoma, lattice dystrophy (lattice dystrophy), retinitis pigmentosa, age-related macular degeneration (AMD), photoreceptor degeneration associated with wet AMD or dry AMD (photoreceptor degeneration), other retinal degenerations, drusen of the optic nerve (optic nerve drusen), optic neuropathy and optic neuritis.
Various embodiments are directed to methods of treating age-related macular degeneration (AMD), the methods comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein.
Some embodiments are directed to methods of treating wet age-related macular degeneration (wet AMD), the methods comprising administering to a subject in need thereof a therapeutically effective amount of a compound as described herein.
Some embodiments are directed to methods of treating dry age-related macular degeneration (dry AMD), the methods comprising administering to a subject in need thereof a therapeutically effective amount of a compound as described herein.
Some embodiments are directed to methods of treating Geographic Atrophy (GA) dry age-related macular degeneration (AMD), the methods comprising administering to a subject in need thereof a therapeutically effective amount of a compound as described herein.
Some embodiments are directed to methods of preventing cell death in neuronal cells, the methods comprising administering to a subject in need thereof a therapeutically effective amount of a compound as described herein.
Some embodiments are directed to methods of preventing cell death in retinal pigment epithelial cells (RPEs), the methods comprising administering to a subject in need thereof a therapeutically effective amount of a compound as described herein.
Some embodiments are directed to methods of preventing cell death in Retinal Ganglion Cells (RGCs), the methods comprising administering to a subject in need thereof a therapeutically effective amount of a compound as described herein.
In some embodiments, a compound according to any of the embodiments described herein may prevent cell dysfunction in Retinal Pigment Epithelial (RPE) cells and Retinal Ganglion Cells (RGCs) associated with dry AMD. In some embodiments, a compound according to any of the embodiments described herein may prevent cell dysfunction associated with dry AMD. In some embodiments, a compound according to any of the embodiments described herein may prevent cellular dysfunction associated with dry AMD, wherein cellular dysfunction may be caused by exposure to inflammatory stimuli, aβ oligomers, 4-hydroxy nonenal or 4-hydroxy-2-nonene (4-HNE), hydrogen peroxide, oxidative stress, and the activity of complement C3.
Some embodiments are directed to methods of treating or preventing oxidative stress in an RPE and an RGC, the methods comprising administering to a subject in need thereof a therapeutically effective amount of a compound as described herein.
In some embodiments, oxidative stress in the RPE and RGC causes cell damage. In some embodiments, the cell damage is selected from the group consisting of: cytotoxicity, lipid peroxidation, carbonyl formation, formation of reactive oxygen species, changes in mitochondrial membrane potential, changes in mitochondrial mass, changes in mitochondrial function, changes in autophagy flux, loss of lysosomal integrity, changes in lysosomal activity, defects in Photoreceptor Outer Segment (POS) transport, accumulation of toxic macromolecules, axonal damage, cell aging, apoptosis, and cell death. In some embodiments, the method of treating or preventing oxidative stress comprises administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising any of the compounds described herein.
Some embodiments are directed to methods of treating or preventing cytotoxicity in an RPE and RGC, the methods comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds as described herein.
Some embodiments are directed to methods of treating or preventing a change in lysosomal activity in an RPE and an RGC, the method comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds as described herein.
Some embodiments are directed to methods of treating or preventing a change in autophagy flux in an RPE and an RGC, the method comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds as described herein.
Some embodiments are directed to methods of treating or preventing defects in Photoreceptor Outer Segment (POS) transport in an RPE, the methods comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds as described herein.
Some embodiments are directed to methods of preventing cell death in RPE and RGC, the methods comprising administering to a subject in need thereof a therapeutically effective amount of any compound as described herein.
Some embodiments are directed to methods of preventing apoptosis in RPE and RGC, the methods comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds as described herein.
Some embodiments are directed to methods of treating or preventing complement C3 dysfunction in RPE and RGC, the methods comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds as described herein.
In some embodiments, complement C3 dysfunction in RPE and RGC causes cellular damage. In some embodiments, the cell damage is selected from the group consisting of cell death, a defect in transepithelial electrical resistance (TEER), and a defect in RPE disorder.
Some embodiments are directed to methods of treating or preventing inflammation in an RPE and an RGC, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound as described herein.
In some embodiments, the inflammation is caused by an inflammatory stimulus. In some embodiments, the inflammatory stimulus is selected from the group consisting of: tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFNg), 4-hydroxynonenal or 4-hydroxy-2-nonene, rotenone, t-butyl hydroperoxide and hydrogen peroxide. In some embodiments, disclosed herein are methods of treating or preventing inflammation caused by any inflammatory stimulus.
Some embodiments are directed to methods of slowing the progression of dry age-related macular degeneration (dry AMD), the methods comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds as described herein.
Some embodiments are directed to methods of preventing dry age-related macular degeneration (dry AMD), the methods comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds as described herein.
Some embodiments are directed to methods of slowing the progression of symptoms associated with dry age-related macular degeneration (dry AMD), the methods comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds as described herein.
In some embodiments, the symptom associated with dry age-related macular degeneration (dry AMD) is selected from the group consisting of: the number of drusen, the drusen size, intraocular hypertension and vision loss. In some embodiments, a method of treating or preventing a symptom associated with dry AMD as described herein comprises administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising any of the compounds as described herein.
Compounds for use in the present invention
In some embodiments, the compound used in the present invention is a compound selected from the group consisting of:
a: the compound of the formula I is a compound of formula I,
or a pharmaceutically acceptable salt thereof:
wherein:
R 1 and R is 2 Each of which is independently selected from H, C 1 -C 6 Alkyl, or CH 2 OR'; wherein if R is 1 And R is 2 R 'is present in each R' is independently H or C 1 -C 6 An alkyl group;
R 3 、R 4 、R 5 and R 6 Independently selected from the group consisting of: H. c (C) 1 -C 6 Alkyl, OH, OCH 3 、OCH(CH 3 ) 2 、OCH 2 CH(CH 3 ) 2 、OC(CH 3 ) 3 、O(C 1 -C 6 Alkyl group, OCF 3 、OCH 2 CH 2 OH、O(C 1 -C 6 Alkyl) OH, O (C) 1 -C 6 Haloalkyl), F, cl, br, I, CF 3 、CN、NO 2 、NH 2 、C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Alkoxy C 1 -C 6 Alkyl, aryl, heteroaryl, C 3 -C 7 Cycloalkyl, heterocycloalkyl, alkylaryl, CO 2 R’、C(O)R’、NH(C 1 -C 4 Alkyl), N (C) 1 -C 4 Alkyl group 2 、NH(C 3 -C 7 Cycloalkyl), NHC (O) (C 1 -C 4 Alkyl), CONR' 2 、NC(O)R'、NS(O) n R'、S(O) n NR' 2 、S(O) n R'、C(O)O(C 1 -C 4 Alkyl), OC (O) N (R') 2 、C(O)(C 1 -C 4 Alkyl), and C (O) NH (C) 1 -C 4 An alkyl group); wherein if R is 3 、R 4 、R 5 And R 6 Wherein R 'is present, each R' is independently selected from the group consisting of: H. CH (CH) 3 、CH 2 CH 3 、C 3 -C 6 Alkyl, C 1 -C 6 Haloalkyl, or optionally substituted aryl, alkylaryl, piperazin-1-yl, piperidin-1-yl, morpholinyl, heterocycloalkyl, heteroaryl, C 1 -C 6 Alkoxy, NH (C) 1 -C 4 Alkyl), and N (C) 1 -C 4 Alkyl group 2 Wherein the optionally substituted group is selected from C 1 -C 6 Alkyl or C 2 -C 7 An acyl group;
or R is 3 And R is 4 Forms, together with the C atom to which they are attached, a 4-membered, 5-membered, 6-membered, 7-membered or 8-membered cycloalkyl, aryl, heteroaryl or heterocycloalkyl group optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from: OH, amino, halogen、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl, or R 3 And R is 4 Are joined to form-O-C 1 -C 2 methylene-O-groups;
or R is 4 And R is 5 Forms, together with the C atom to which they are attached, a 4-membered, 5-membered, 6-membered, 7-membered or 8-membered cycloalkyl, aryl, heteroaryl or heterocycloalkyl group optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from: OH, amino, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl, or R 4 And R is 5 Are joined to form-O-C 1-2 methylene-O-groups;
R 7 、R 8 、R 9 、R 10 and R 11 Independently selected from the group consisting of: H. c (C) 1 -C 6 Alkyl, OH, OCH 3 、OCH(CH 3 ) 2 、OCH 2 CH(CH 3 ) 2 、OC(CH 3 ) 3 、O(C 1 -C 6 Alkyl group, OCF 3 、OCH 2 CH 2 OH、O(C 1 -C 6 Alkyl) OH, O (C) 1 -C 6 Haloalkyl), O (CO) R', F, cl, br, I, CF 3 、CN、NO 2 、NH 2 、C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Alkoxy C 1 -C 6 Alkyl, aryl, heteroaryl, C 3 -C 7 Cycloalkyl, heterocycloalkyl, alkylaryl, heteroaryl, CO 2 R’、C(O)R’、NH(C 1 -C 4 Alkyl), N (C) 1 -C 4 Alkyl group 2 、NH(C 3 -C 7 Cycloalkyl), NHC (O) (C 1 -C 4 Alkyl group)、CONR' 2 、NC(O)R'、NS(O) n R'、S(O) n NR' 2 、S(O) n R'、C(O)O(C 1 -C 4 Alkyl), OC (O) N (R') 2 、C(O)(C 1 -C 4 Alkyl), and C (O) NH (C) 1 -C 4 An alkyl group); wherein if R is 7 、R 8 、R 9 、R 10 And R 11 Wherein R 'is present, each R' is independently selected from the group consisting of: H. CH (CH) 3 、CH 2 CH 3 、C 3 -C 6 Alkyl, C 1 -C 6 Haloalkyl, aryl, alkylaryl, piperazin-1-yl, piperidin-1-yl, morpholinyl, heterocycloalkyl, heteroaryl, C 1 -C 6 Alkoxy, NH (C) 1 -C 4 Alkyl), and N (C) 1 -C 4 Alkyl group 2 ；
Or R is 7 And R is 8 Forms, together with the N or C atom to which they are attached, a 4-, 5-, 6-, 7-, or 8-membered cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from: OH, amino, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl, or R 7 And R is 8 Are joined to form-O-C 1-2 methylene-O-groups;
or R is 8 And R is 9 Forms, together with the N or C atom to which they are attached, a 4-, 5-, 6-, 7-, or 8-membered cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from: OH, amino, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl, or R 8 And R is 9 Are joined to form-O-C 1-2 Methylene (S)A group-O-group;
each n is independently 0, 1, or 2;
with the proviso that R 7 、R 8 、R 9 、R 10 And R 11 Not all H; and is also provided with
With the proviso that the following compounds or pharmaceutically acceptable salts thereof are excluded:
Or alternatively
B: compounds of formula IA
Or a pharmaceutically acceptable salt thereof:
wherein:
R a 、R b 、R c 、R d and R is e Each of which is independently selected from the group consisting of H, hydroxy, cl, F, methyl, -OCH 3 、-OC(CH 3 ) 3 、O-CH(CH 3 ) 2 、CF 3 、SO 2 CH 3 And morpholino;
R 1A selected from the group consisting of: hydrogen, alkyl, phenyl, or-ch=c (CH 3 ) 2 The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with
R 2A Is an optionally substituted cyclic amino group.
Compounds of formula I
In some embodiments, the compounds used in the present invention are selected from compounds of formula I:
or a pharmaceutically acceptable salt thereof:
wherein:
R 1 and R is 2 Each of which is independently selected from H, C 1 -C 6 Alkyl, or CH 2 OR'; wherein if R is 1 And R is 2 R 'is present in each R' is independently H or C 1 -C 6 An alkyl group;
R 3 、R 4 、R 5 and R 6 Independently selected from the group consisting of: H. c (C) 1 -C 6 Alkyl, OH, OCH 3 、OCH(CH 3 ) 2 、OCH 2 CH(CH 3 ) 2 、OC(CH 3 ) 3 、O(C 1 -C 6 Alkyl group, OCF 3 、OCH 2 CH 2 OH、O(C 1 -C 6 Alkyl) OH, O (C) 1 -C 6 Haloalkyl), F, cl, br, I, CF 3 、CN、NO 2 、NH 2 、C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Alkoxy C 1 -C 6 Alkyl, aryl, heteroaryl, C 3 -C 7 Cycloalkyl, heterocycloalkyl, alkylaryl, CO 2 R’、C(O)R’、NH(C 1 -C 4 Alkyl), N (C) 1 -C 4 Alkyl group 2 、NH(C 3 -C 7 Cycloalkyl), NHC (O) (C 1 -C 4 Alkyl), CONR' 2 、NC(O)R'、NS(O) n R'、S(O) n NR' 2 、S(O) n R'、C(O)O(C 1 -C 4 Alkyl), OC (O) N (R') 2 、C(O)(C 1 -C 4 Alkyl), and C (O) NH (C) 1 -C 4 An alkyl group); wherein if R is 3 、R 4 、R 5 And R 6 Wherein R 'is present, each R' is independently selected from the group consisting of: H. CH (CH) 3 、CH 2 CH 3 、C 3 -C 6 Alkyl, C 1 -C 6 Haloalkyl, or optionally substituted aryl, alkylaryl, piperazin-1-yl, piperidin-1-yl, morpholinyl, heterocycloalkyl, heteroaryl, C 1 -C 6 Alkoxy, NH (C) 1 -C 4 Alkyl), and N (C) 1 -C 4 Alkyl group 2 Wherein the optionally substituted group is selected from C 1 -C 6 Alkyl or C 2 -C 7 An acyl group;
or R is 3 And R is 4 Forms, together with the C atom to which they are attached, a 4-membered, 5-membered, 6-membered, 7-membered or 8-membered cycloalkyl, aryl, heteroaryl or heterocycloalkyl group optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from: OH, amino, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl, or R 3 And R is 4 Are joined to form-O-C 1 -C 2 methylene-O-groups;
or R is 4 And R is 5 Forms, together with the C atom to which they are attached, a 4-membered, 5-membered, 6-membered, 7-membered or 8-membered cycloalkyl, aryl, heteroaryl or heterocycloalkyl group optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from: OH, amino, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl, or R 4 And R is 5 Are joined to form-O-C 1-2 methylene-O-groups;
R 7 、R 8 、R 9 、R 10 and R 11 Independently selected from the group consisting of: H. c (C) 1 -C 6 Alkyl, OH, OCH 3 、OCH(CH 3 ) 2 、OCH 2 CH(CH 3 ) 2 、OC(CH 3 ) 3 、O(C 1 -C 6 Alkyl group, OCF 3 、OCH 2 CH 2 OH、O(C 1 -C 6 Alkyl) OH, O (C) 1 -C 6 Haloalkyl), O (CO) R', F, cl、Br、I、CF 3 、CN、NO 2 、NH 2 、C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Alkoxy C 1 -C 6 Alkyl, aryl, heteroaryl, C 3 -C 7 Cycloalkyl, heterocycloalkyl, alkylaryl, heteroaryl, CO 2 R’、C(O)R’、NH(C 1 -C 4 Alkyl), N (C) 1 -C 4 Alkyl group 2 、NH(C 3 -C 7 Cycloalkyl), NHC (O) (C 1 -C 4 Alkyl), CONR' 2 、NC(O)R'、NS(O) n R'、S(O) n NR' 2 、S(O) n R'、C(O)O(C 1 -C 4 Alkyl), OC (O) N (R') 2 、C(O)(C 1 -C 4 Alkyl), and C (O) NH (C) 1 -C 4 Alkyl), wherein if R 7 、R 8 、R 9 、R 10 And R 11 Wherein R 'is present, each R' is independently selected from the group consisting of: H. CH (CH) 3 、CH 2 CH 3 、C 3 -C 6 Alkyl, C 1 -C 6 Haloalkyl, aryl, alkylaryl, piperazin-1-yl, piperidin-1-yl, morpholinyl, heterocycloalkyl, heteroaryl, C 1 -C 6 Alkoxy, NH (C) 1 -C 4 Alkyl), and N (C) 1 -C 4 Alkyl group 2 ；
Or R is 7 And R is 8 Forms, together with the N or C atom to which they are attached, a 4-, 5-, 6-, 7-, or 8-membered cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from: OH, amino, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl, or R 7 And R is 8 Are joined to form-O-C 1-2 methylene-O-groups;
or R is 8 And R is 9 With the N or C atom to which they are attachedCycloalkyl, aryl, heterocycloalkyl or heteroaryl groups which together form 4-, 5-, 6-, 7-, or 8-membered optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from: OH, amino, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl, or R 8 And R is 9 Are joined to form-O-C 1-2 methylene-O-groups;
each n is independently 0, 1, or 2;
with the proviso that R 7 、R 8 、R 9 、R 10 And R 11 Not all H; and is also provided with
With the proviso that the following compounds or pharmaceutically acceptable salts thereof are excluded:
in some embodiments, the compounds used in the present invention are compounds of formula I, or a pharmaceutically acceptable salt thereof, wherein R 1 And R is 2 Each independently selected from H or CH 3 ；R 3 、R 4 、R 5 And R 6 Each independently selected from the group consisting of: H. c (C) 1 -C 6 Alkyl, OH, OCH 3 、O(C 1 -C 6 Alkyl group), O (C) 1 -C 6 Haloalkyl), F, cl, CF 3 Aryl, heteroaryl, C 3 -C 7 Cycloalkyl, CO 2 R’、C(O)R’、OC(O)N(R’) 2 、CONR' 2 、NC(O)R'、NS(O) n R'、S(O) n NR' 2 、S(O) n R'; wherein n=0, 1, or 2; r' are each independently H, CH 3 、CH 2 CH 3 、C 3 -C 6 Alkyl, C 1 -C 6 Haloalkyl, or optionally substituted piperazin-1-yl, piperidin-1-yl, morpholinyl, heterocycloalkyl,Or aryl, wherein the optionally substituted group is selected from C 1 -C 6 Alkyl or C 2 -C 7 An acyl group; or R is 3 And R is 4 Form a 5-or 6-membered C together with the C atom to which they are attached 3-7 Cycloalkyl, or aryl; or R is 4 And R is 5 Together with the C atom to which they are attached form C 3-7 Cycloalkyl, or 5-, or 6-membered aryl, or R 3 And R is 4 Are joined to form-O-C 1-2 methylene-O-groups; or R is 4 And R is 5 Are joined to form-O-C 1-2 methylene-O-groups; and R is 7 、R 8 、R 9 、R 10 And R 11 Each of which is independently selected from H, OH, CH 3 、CH 2 CH 3 、F、Cl、CF 3 、OCF 3 、C 1 -C 6 Haloalkyl, OCH 3 、O(C 1 -C 6 Alkyl group, OCH 2 CH 2 OH、O(C 1 -C 6 Alkyl) OH, aryl, heteroaryl, C 3 -C 7 Cycloalkyl, alkylaryl, CO 2 R’、CONR' 2 、S(O) n NR' 2 、S(O) n R'、C(O)O(C 1 -C 4 Alkyl), OC (O) N (R') 2 And C (O) NH (C) 1 -C 4 An alkyl group); wherein n=0, 1, or 2; r' are each independently H, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, aryl, alkylaryl, or C 1 -C 6 An alkoxy group.
In some embodiments, the compounds used in the present invention are compounds of formula I, or a pharmaceutically acceptable salt thereof, wherein R 7 、R 10 、R 11 Each is H; r is R 3 And R is 4 Each independently selected from H, F, cl, S (O) n R ', C (O) R ', wherein n=2, and R ' is selected from CH 3 Piperazin-1-yl, piperidin-1-yl, morpholinyl; r is R 8 Selected from OH, OCH 3 、OCH(CH 3 ) 2 、OCH 2 CH(CH 3 ) 2 Or OC (CH) 3 ) 3 The method comprises the steps of carrying out a first treatment on the surface of the And R is 9 Is OH。
In some embodiments, the compounds used in the present invention are compounds of formula I selected from the group consisting of:
/>
in further embodiments, the compound used in the present invention is a compound of formula II, or a pharmaceutically acceptable salt thereof:
wherein R is 3 、R 4 、R 5 And R 6 Each independently selected from the group consisting of: H. cl, F, OH, CH 3 、C 1 -C 6 Alkyl, OCH 3 、OCH(CH 3 ) 2 、OCH 2 CH(CH 3 ) 2 、OC(CH 3 ) 3 、OC 1 -C 6 Alkyl, aryl, heteroaryl, heterocycloalkyl, CO 2 R’、CONR' 2 、NC(O)R'、NS(O) n R'、S(O) n NR' 2 、S(O) n R'、C(O)R’、OC(O)N(R’) 2 Or C (O) NH (C) 1 -C 4 Alkyl), wherein n=0, 1, or 2; and R' are each independently H, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, or optionally substituted aryl, alkylaryl, piperazin-1-yl, piperidin-1-yl, morpholinyl, heterocycloalkyl, heteroaryl, C 1 -C 6 Alkoxy, NH (C) 1 -C 4 Alkyl), or NH (C) 1 -C 4 Alkyl group 2 Wherein the optionally substituted group is selected from C 1 -C 6 Alkyl or C 2 -C 7 An acyl group;
or R is 3 And R is 4 Together with the C atom to which they are attached, form a 6-membered aryl group; or R is 3 And R is 4 Are joined to form-O-C 1-2 methylene-O-groups; or R is 4 And R is 5 Together with the C atom to which they are attached, form a 6-membered aryl group; or R is 4 And R is 5 Are joined to form-O-C 1-2 methylene-O-groups; and is also provided with
R 8 And R is 9 Each independently selected from the group consisting of: H. cl, F, OH, CH 3 、C 1 -C 6 Alkyl, OCH 3 、OCH(CH 3 ) 2 、OCH 2 CH(CH 3 ) 2 、OC(CH 3 ) 3 、O(CO)R’、OC 1 -C 6 Alkyl, aryl, heteroaryl, heterocycloalkyl, CO 2 R’、CONR' 2 、NC(O)R'、NS(O) n R'、S(O) n NR' 2 、S(O) n R'、OC(O)N(R’) 2 Or C (O) NH (C) 1 -C 4 An alkyl group);
or R is 8 And R is 9 Forms, together with the N or C atom to which they are attached, a 4-, 5-, 6-, 7-, or 8-membered cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from: OH, amino, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl, and R 9 And R is 10 Each independently selected from the group consisting of bond, C, N, S, and O; or R is 8 And R is 9 Are joined to form-O-C 1-2 methylene-O-groups.
In further embodiments, the compounds used in the present invention are compounds of formula II, or a pharmaceutically acceptable salt thereof, wherein R 3 、R 4 、R 5 And R is 6 At least one of which is other than H; and R is 8 And R is 9 At least one of which is other than H.
In other embodiments, the compounds used in the present invention are compounds of formula II, or a pharmaceutically acceptable salt thereof, wherein R 7 、R 10 、R 11 Each is H; r is R 3 And R is 4 Each independently selected from H, F, cl, S (O) n R ', C (O) R ', wherein n=2, and R ' is selected from CH 3 Or optionally substituted piperazin-1-yl, piperidin-1-yl, or morpholinyl, wherein the optionally substituted group is selected from C 1 -C 6 Alkyl or C 2 -C 7 An acyl group; r is R 8 Selected from OH, cl, OCH 3 、OCH(CH 3 ) 2 、OCH 2 CH(CH 3 ) 2 Or OC (CH) 3 ) 3 The method comprises the steps of carrying out a first treatment on the surface of the And R is 9 OH or Cl.
In further embodiments, the compounds used in the present invention are compounds of formula II, or a pharmaceutically acceptable salt thereof, wherein R 3 And R is 4 Each independently selected from H, F, cl, S (O) n R ', C (O) R ', wherein n=2, and R ' is selected from CH 3 Piperazin-1-yl, piperidin-1-yl, or morpholinyl; r is R 5 And R is 6 Each is H; r is R 8 Selected from OH, OCH 3 、OCH(CH 3 ) 2 、OCH 2 CH(CH 3 ) 2 Or OC (CH) 3 ) 3 The method comprises the steps of carrying out a first treatment on the surface of the And R is 9 Is OH.
In further embodiments, the compound used in the present invention or a pharmaceutically acceptable salt thereof is selected from the group consisting of:
/>
/>
/>
in further embodiments, the compound used in the present invention or a pharmaceutically acceptable salt thereof is a compound selected from the group consisting of:
in further embodiments, the compound used in the present invention or a pharmaceutically acceptable salt thereof is a compound selected from the group consisting of:
In some embodiments, the compounds used in the present invention are:
or a pharmaceutically acceptable salt thereof.
In some embodiments, the compounds used in the present invention are:
in some embodiments, the compound used in the present invention, or a pharmaceutically acceptable salt thereof, is a compound of formula I, wherein R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 And R 11 With the proviso that when R is as defined herein 1 、R 3 、R 6 、R 7 、R 10 And R is 11 Each is H; r is R 2 Is CH 3 ；R 8 Is OCH 3 Or Cl; and R is 9 In the case of OH or Cl, R 4 Not being Cl or CF 3 And R is 5 Not being Cl or CF 3 。
In some embodiments, the compound used in the present invention is a compound of formula II:
or a pharmaceutically acceptable salt thereof,
wherein R is 3 、R 4 、R 5 、R 6 、R 8 And R 9 As defined herein.
In another embodiment, the compound used in the present invention is a compound of formula III:
or a pharmaceutically acceptable salt thereof, wherein R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 And R is 11 As provided herein, and wherein eachIndependently selected from single, double or triple bonds.
In some aspects, the compound used in the present invention is a compound according to formula III selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
In some embodiments, the compounds useful in the present invention include racemic mixtures or enantiomers of compounds of formula I wherein R 3 、R 4 、R 5 、R 6 、R 8 And R 9 As described herein.
In some embodiments, the compounds useful in the present invention include compounds of formula I or pharmaceutically acceptable salts thereof, wherein R 8 And R is 9 Independently selected from OH, C 1-6 Alkoxy, and hydroxy C 1-6 An alkoxy group.
In some embodiments, the compounds useful in the present invention include compounds of formula I or pharmaceutically acceptable salts thereof, wherein R 8 And R is 9 Independently selected from OH and NH (C) 1-4 Alkyl).
In some embodiments, the compounds useful in the present invention include compounds of formula I or pharmaceutically acceptable salts thereof, wherein R 8 And R is 9 Independently selected from H, halogen, C 1-6 Haloalkyl, or C 1-6 Haloalkoxy groups.
In some embodiments, the compounds useful in the present invention include compounds of formula I or pharmaceutically acceptable salts thereof, wherein R 8 And R is 9 Each independently selected from OH, halogen, C 1-6 Alkoxy and C 1-6 Haloalkoxy and R 1 And R is 2 Each independently is C 1-6 An alkyl group.
In some embodiments, the compounds useful in the present invention include compounds of formula I or pharmaceutically acceptable salts thereof, wherein R 1 And R is 2 Each methyl.
In some embodiments, the compounds useful in the present invention include compounds of formula I or pharmaceutically acceptable salts thereof, wherein R 1 And R is 2 One of which is methyl and the other is H.
In some embodiments, the compounds useful in the present invention include compounds of formula I or pharmaceutically acceptable salts thereof, wherein R 8 And R is 9 Each independently selected from OH or C 1-6 Alkoxy and R 1 And R is 2 Each independently is methyl.
In some embodiments, the compounds useful in the present invention include compounds of formula IOr a pharmaceutically acceptable salt thereof, wherein R 8 And R is 9 Independently selected from H, halogen, and C 1-6 Haloalkyl and R 1 And R is 2 Each methyl.
In some embodiments, the compounds useful in the present invention include compounds of formula I or pharmaceutically acceptable salts thereof, wherein R 8 And R is 9 Each independently selected from H, halogen and C 1-6 A haloalkyl group.
In some embodiments, the compounds useful in the present invention include compounds of formula I or pharmaceutically acceptable salts thereof, wherein R 7 And R is 11 Each is H.
In some embodiments, the compounds useful in the present invention include compounds of formula I or pharmaceutically acceptable salts thereof, wherein R 3 、R 4 、R 5 And R 6 Each independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 An alkoxy group.
In some embodiments, the compounds useful in the present invention include compounds of formula I or pharmaceutically acceptable salts thereof, wherein R 3 、R 4 And R is 5 Each independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 An alkoxy group.
In some embodiments, the compounds useful in the present invention include compounds of formula I or pharmaceutically acceptable salts thereof, wherein R 3 、R 4 、R 5 And R 6 Each independently selected from H, halogen, S (O) n R'、C(O)OR’、C(O)N(R’) 2 And C (O) R'; wherein n=2; r' are each independently H, CH 3 、CH 2 CH 3 、C 3 -C 6 Alkyl, C 1 -C 6 Haloalkyl, or alternatively C 1 -C 6 Alkyl or C 2 -C 7 Acyl substituted aryl, alkylaryl, piperazinyl, piperidinyl, morpholinyl, heterocycloalkyl, and heteroaryl.
In some embodiments, the compounds useful in the present invention include the chemical formula IA compound or pharmaceutically acceptable salt thereof, wherein R 3 、R 4 And R is 5 Each independently selected from H, halogen, S (O) n R ', and C (O) R'; wherein n=2; r' are each independently CH 3 、CH 2 CH 3 、C 3 -C 6 Alkyl, aryl, piperazin-1-yl, piperidin-1-yl, and morpholin-4-yl.
In some embodiments, the compounds useful in the present invention include compounds of formula I or pharmaceutically acceptable salts thereof, wherein R 3 、R 4 And R is 5 Each independently selected from H, halogen, S (O) n R ', and C (O) R'; wherein n=2; r' are each independently CH 3 、CH 2 CH 3 、C 3 -C 6 Alkyl, aryl, piperazin-1-yl, piperidin-1-yl, and morpholin-4-yl; r is R 8 And R is 9 Each independently selected from OH, halogen, C 1-6 Alkoxy and C 1-6 Haloalkoxy groups; and R is 1 And R is 2 Each methyl.
In some embodiments, the compounds useful in the present invention include compounds of formula I or pharmaceutically acceptable salts thereof, wherein R 3 And R is 4 Or R is 4 And R is 5 Together with the C atom to which they are attached, form a 6-membered cycloalkyl, or heterocycloalkyl, aryl or heteroaryl ring.
In some embodiments, the compounds useful in the present invention include compounds of formula I or pharmaceutically acceptable salts thereof, wherein R 3 And R is 4 Or R is 4 And R is 5 Is O, and are joined to form-O-C 1-2 methylene-O-groups.
In some embodiments, the compounds useful in the present invention include compounds of formula I or pharmaceutically acceptable salts thereof, wherein R 2 And R is 3 Independently selected from H, OH, halogen, C 1-6 Alkoxy and C 1-6 A haloalkyl group.
In some embodiments, the compounds used in the present invention include compounds of formula II or pharmaceutically acceptable salts thereof, wherein R 3 And R is 4 Independently selected from H, cl, F, -OMe,-CF 3 、S(O) n R ', and C (O) R'; wherein n=2, and R' are each independently H, CH 3 、CH 2 CH 3 、C 3 -C 6 Alkyl, aryl, piperazin-1-yl, piperidin-1-yl, and morpholin-4-yl; r is R 8 And R is 9 Each independently selected from OH and C 1-6 An alkoxy group.
In some embodiments, the compounds useful in the present invention include compounds of formula I or pharmaceutically acceptable salts thereof, wherein R 2 And R is 3 Independently selected from H, OH, cl, F, -OMe and-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 7 And R is 8 Each independently selected from H and C 1-6 An alkyl group; wherein R is 9 Is H, and wherein R 5 And R is 6 Each independently selected from H and C 1-6 A haloalkyl group.
In some embodiments, any of the compounds of formulas I-III according to any of the embodiments described herein may contain the additional clauses of removing one or more of the following compounds:
compounds of formula IA
In some embodiments, the compounds useful in the present invention include compounds of formula IA
Or a pharmaceutically acceptable salt thereof:
wherein:
R a 、R b 、R c 、R d and R is e Independently selected from the group consisting of: H. hydroxy, cl, F, methyl, -OCH 3 、-OC(CH 3 ) 3 、O-CH(CH 3 ) 2 、CF 3 、SO 2 CH 3 And morpholino;
R 1A selected from the group consisting ofThe group: hydrogen, alkyl, phenyl, or-ch=c (CH 3 ) 2 The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with
R 2A Is an optionally substituted cyclic amino group.
In some embodiments, compounds useful in the present invention include compounds of formula IA wherein the substituents R a 、R b 、R c 、R d And R is e Independently selected from the group consisting of: H. hydroxy, cl, F, methyl, -OCH 3 、-OC(CH 3 ) 3 、O-CH(CH 3 ) 2 、CF 3 、SO 2 CH 3 And morpholino.
In some embodiments, compounds useful in the present invention include compounds of formula IA wherein the substituents R a 、R b 、R c 、R d And R is e Independently selected from the group consisting of: H. cl, F, and CF 3 。
In some embodiments, compounds useful in the present invention include compounds of formula IA wherein the substituents R a 、R b 、R d And R is e Independently is H; and R is c Selected from the group consisting of: H. hydroxy, halogen, alkyl, alkoxy, CF 3 、SO 2 CH 3 And morpholino;
in some embodiments, compounds useful in the present invention include compounds of formula IA wherein the substituents R a 、R b 、R d And R is e Independently is H; and R is c Selected from the group consisting of: H. hydroxy, cl, F, methyl, -OCH 3 、-OC(CH 3 ) 3 、O-CH(CH 3 ) 2 、CF 3 、SO 2 CH 3 And morpholino.
In some embodiments, compounds useful in the present invention include compounds of formula IA wherein the substituents R a 、R b 、R d And R is e Independently is H; and R is c Selected from the group consisting of: H. cl, F, and CF 3 。
In various embodiments, compounds useful in the present invention include compounds of formula IA wherein R 2A Is any heterocycloalkyl or heteroaryl group containing nitrogen in the ring, which is bound to the aliphatic chain of formula IA through a nitrogen atom. In some embodiments, for example, R 2A Is an optionally substituted cyclic amino group selected from the group consisting of:
and the like,
wherein each nitrogen-containing heterocycloalkyl or nitrogen-containing heteroaryl may be optionally substituted with one or more substituents selected from the group consisting of: hydroxy, halogen, CF 3 Alkoxy, aryloxy, optionally substituted C 1 -C 10 Alkyl, optionally substituted C 5 -C 10 Aryl, optionally substituted C 3 -C 10 Heteroaryl, substituted or unsubstituted C 3 -C 10 Cycloalkyl or heterocycloalkyl.
In various embodiments, compounds useful in the present invention include compounds of formula IA wherein R 2A Selected from the group consisting of: optionally substituted aziridinyl, optionally substituted pyrrolidinyl, optionally substituted imidazolidinyl, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted oxopiperazinyl, and optionally substituted morpholinyl.
In some embodiments, the compounds useful in the present invention include compounds of formula IA wherein when R 2A When a cyclic amino group is substituted, one or more of the hydrogen atoms in the cyclic amino group is replaced with a group selected from the group consisting of: alkanoyl, alkoxy, alkoxyalkyl, (alkoxy) alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, aroyl (aryloyl), cycloalkanoyl, -OC (O) NCH (CH) 3 ) 2 (N, N-dimethylamino) pyridinyl, (N, N-dimethylamino) sulfonyl, halogen, heterocyclyl, (heterocyclyl) alkoxyalkyl, hydroxy, hydroxyalkyl, methylpiperidinyl, methylsulfonyl, methylsulfonylphenyl, morpholinylpyridinyl, perfluoroalkyl, phenyl, piperidinyl, pyrrolidinylpyridinyl, tetrahydropyranyl, and CF 3 . In some embodiments, the metal is selected fromThe two hydrogen atoms on the same carbon of the cyclic amino group are replaced to form a spiro compound. />
In some embodiments, the compounds useful in the present invention include compounds of formula IA wherein R 2A Is pyrrolidinyl or substituted pyrrolidinyl substituted with one or more substituents selected from the group consisting of alkoxyalkyl, alkoxycarbonyl, alkyl, hydroxy, and hydroxyalkyl. In some embodiments, R 2A Is a substituted pyrrolidinyl group substituted with a single substituent selected from the group consisting of alkoxyalkyl, alkoxycarbonyl, alkyl, hydroxy, and hydroxyalkyl. In some embodiments, R 2A Is a substituted pyrrolidinyl group substituted with a single substituent selected from the group consisting of hydroxy, hydroxymethyl, methoxymethyl, methoxycarbonyl, and methyl.
In some embodiments, the compounds useful in the present invention include compounds of formula IA wherein R 2A Is piperidinyl or substituted piperidinyl substituted with one or more substituents selected from alkoxy, alkoxyalkyl, (alkoxy) alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, -OC (O) NCH (CH) 3 ) 2 (N, N-dimethylamino) pyridinyl, halogen, heterocyclyl, (heterocyclyl) alkoxyalkyl, hydroxy, hydroxyalkyl, methylpiperidinyl, methylsulfonylphenyl, morpholinylpyridinyl, perfluoroalkyl, phenyl, piperidinyl, pyrrolidinylpyridinyl, tetrahydropyranyl and CF 3 A group of groups. In some embodiments, R 2A Is piperidinyl groupOr substituted piperidinyl substituted with a single substituent selected from the group consisting of alkoxy, alkoxyalkyl, (alkoxy) alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, -OC (O) NCH (CH) 3 ) 2 (N, N-dimethylamino) pyridinyl, halogen, heterocyclyl, (heterocyclyl) alkoxyalkyl, hydroxy, hydroxyalkyl, methylpiperidinyl, methylsulfonylphenyl, morpholinylpyridinyl, perfluoroalkyl, phenyl, piperidinyl, pyrrolidinylpyridinyl, tetrahydropyranyl and CF 3 A group of groups. In some embodiments, R 2A Is piperidinyl or substituted piperidinyl substituted with a single substituent selected from the group consisting of alkoxy, alkoxyalkyl, (alkoxy) alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, -OC (O) NCH (CH) 3 ) 2 (N, N-dimethylamino) pyridinyl, halogen, heterocyclyl, (heterocyclyl) alkoxyalkyl, hydroxy, hydroxyalkyl, methylpiperidinyl, methylsulfonylphenyl, morpholinylpyridinyl, perfluoroalkyl, phenyl, piperidinyl, pyrrolidinylpyridinyl, tetrahydropyranyl and CF 3 A group of groups. In some embodiments, R 2A Is piperidinyl or substituted piperidinyl substituted with a single substituent selected from methyl, isopropyl, isobutyl, CF 3 Hydroxymethyl, hydroxyethyl, (isopropoxy) ethyl, - (CH) 2 ) 2 O(CH 2 ) 2 OCH 3 、-(CH 2 ) 3 OCH 3 -C (O) OMe, -C (O) OEt, hydroxy, methoxy, isopropoxy, phenyloxy, F, ethoxy, phenyl,
/>A group of groups. In some embodiments, R 2A Is piperidinyl or substituted piperidinyl substituted at position 4 of piperidinyl with a single substituent selected from the group consisting of alkoxy, alkoxyalkyl, (alkoxy) alkoxyalkyl, Alkoxycarbonyl, alkyl, aryloxy, -OC (O) NCH (CH) 3 ) 2 (N, N-dimethylamino) pyridinyl, halogen, heterocyclyl, (heterocyclyl) alkoxyalkyl, hydroxy, hydroxyalkyl, methylpiperidinyl, methylsulfonylphenyl, morpholinylpyridinyl, perfluoroalkyl, phenyl, piperidinyl, pyrrolidinylpyridinyl, tetrahydropyranyl and CF 3 A group of groups. In some embodiments, R 2A Is piperidinyl or substituted piperidinyl substituted at position 4 of piperidinyl with a single substituent selected from methyl, isopropyl, isobutyl, CF 3 Hydroxymethyl, hydroxyethyl, (isopropoxy) ethyl, - (CH) 2 ) 2 O(CH 2 ) 2 OCH 3 、-(CH 2 ) 3 OCH 3 -C (O) OMe, -C (O) OEt, hydroxy, methoxy, isopropoxy, phenyloxy, F, ethoxy, phenyl,
A group of groups.
In some embodiments, the compounds useful in the present invention include compounds of formula IA wherein R 2A Is piperidinyl or substituted piperidinyl substituted on the same carbon as piperidinyl with two substituent groups independently selected from alkoxyalkyl, alkyl, -OC (O) NCH (CH) 3 ) 2 A hydroxyl group and a phenyl group. In some embodiments, R 2A Is piperidinyl or substituted piperidinyl substituted at position 4 of piperidinyl with two substituent groups independently selected from alkoxyalkyl, alkyl, -OC (O) NCH (CH) 3 ) 2 A hydroxyl group and a phenyl group. In some embodiments, R 2A Is piperidinyl or substituted piperidinyl substituted at position 4 with two substituent groups selected from hydroxy and methyl; hydroxy groupA group and an ethyl group; hydroxy and- (CH) 2 ) 2 OCH 3 The method comprises the steps of carrying out a first treatment on the surface of the Hydroxy and phenyl; methyl and phenyl; methyl and-OC (O) NCH (CH) 3 ) 2 The method comprises the steps of carrying out a first treatment on the surface of the Butyl and-OC (O) NCH (CH) 3 ) 2 A group of groups. In some embodiments, the metal is selected fromThe compound of (2) replaces two hydrogen atoms on the same carbon of the piperidinyl group to form a spiro compound. In some embodiments, the polypeptide is selected from +.> Instead of two hydrogen atoms at position 4 of the piperidinyl group to form a spiro compound.
In some embodiments, the compounds useful in the present invention include compounds of formula IA wherein R 2A Is piperazinyl or substituted piperazinyl substituted with one or more substituents selected from the group consisting of alkanoyl, alkoxycarbonyl, aroyl, cycloalkanoyl, (N, N-dimethylamino) sulfonyl, heterocyclyl, methylsulfonyl and phenyl. In some embodiments, R 2A Is a substituted piperazinyl group substituted with a single substituent selected from the group consisting of alkanoyl, alkoxycarbonyl, aroyl, cycloalkanoyl, (N, N-dimethylamino) sulfonyl, heterocyclyl, methylsulfonyl and phenyl. In some embodiments, R 2A Is a substituted piperazinyl group substituted with a single substituent selected from the group consisting of-C (O) OC (CH) 3 ) 3 、-C(O)OCH 2 CH(CH 3 ) 2 、-C(O)OCH 2 CH 3 、-C(O)OCH 3 Phenyl, -C (O) CH 3 、-C(O)Ph、-SO 2 Me、-SO 2 N(CH 3 ) 2 、Composition of the compositionIs a group of (a). In some embodiments, R 2A Is a substituted piperazinyl group substituted at position 4 with a single substituent selected from the group consisting of-C (O) OC (CH) 3 ) 3 、-C(O)OCH 2 CH(CH 3 ) 2 、-C(O)OCH 2 CH 3 、-C(O)OCH 3 Phenyl, -C (O) CH 3 、-C(O)Ph、-SO 2 Me、-SO 2 N(CH 3 ) 2 、A group of groups.
In certain embodiments, the compounds useful in the present invention include compounds of formula IA wherein R 2A Is a substituted piperidinyl group of the formula:
wherein R is 3A Is hydrogen or C 1 -C 8 Alkyl, and R 4A Is hydrogen, hydroxy, halogen, CF 3 Alkoxy, aryloxy, optionally substituted C 1 -C 10 Alkyl, optionally substituted C 5 -C 10 Aryl, optionally substituted C 3 -C 10 Heteroaryl, optionally substituted C 3 -C 10 Cycloalkyl or optionally substituted C 3 -C 10 A heterocycloalkyl group.
In some embodiments, the compounds useful in the present invention include compounds of formula IA wherein R 2A The method comprises the following steps:
wherein R is 5A And R is 6A Each of which is independently hydrogen, hydroxy, sulfonyl, dialkylamino, optionally substituted C 1 -C 10 Alkyl, optionally substituted C 5 -C 10 Aryl, optionally substituted C 3 -C 10 Heteroaryl, optionally substituted C 3 -C 10 Cycloalkyl or optionally substituted C 3 -C 10 A heterocycloalkyl group. In some embodiments, R 5A Is hydrogen, dialkylamino or C 3 -C 10 A heterocycloalkyl group. In some embodiments, R 5A Is hydrogen, dialkylamino, pyrrolidinyl or morpholinyl. In some embodiments, R 6A Is sulfonyl. In some embodiments, R 6A Is methylsulfonyl.
In some embodiments, the compounds useful in the present invention include compounds of formula IA wherein R 2A The method comprises the following steps:
/>
wherein R is 3a Selected from hydrogen and C 1 -C 8 Alkyl groups; and n is A Is an integer selected from 0, 1 and 2.
In some embodiments, the compounds useful in the present invention include compounds of formula IA wherein R 2A The method comprises the following steps:
in some embodiments, the compounds useful in the present invention include compounds of formula IA wherein R 2A Is an optionally substituted morpholinyl group. In some embodiments, R 2A Is morpholinyl.
In some embodiments, the compounds useful in the present invention include compounds of formula IA wherein R 2A Is an optionally substituted piperazinyl of the formula:
wherein R is 7 Is hydrogen, hydroxy, sulfonyl, dialkylaminosulfonyl, alkoxycarbonyl, acyl, benzoyl, cycloalkylcarbonyl, optionally substituted C 1 -C 10 Alkyl, optionally substituted C 5 -C 10 Aryl, optionally substituted C 3 -C 10 Heteroaryl, optionally substituted C 3 -C 10 Cycloalkyl or optionally substituted C 3 -C 10 A heterocycloalkyl group. In some embodiments, R 7A Is sulfonyl, dialkylaminosulfonyl, alkoxycarbonyl, acyl, benzoyl, cycloalkylcarbonyl, C 5 -C 10 Aryl or optionally substituted C 3 -C 10 A heterocycloalkyl group.
In some embodiments, the compounds useful in the present invention include compounds of formula IA wherein R 2A The method comprises the following steps:
in various embodiments, compounds useful in the present invention include compounds of formula IA wherein R 2A Is optionally substituted pyrrolidinyl:
wherein R is 8A Is hydrogen, hydroxy, sulfonyl, optionally substituted C 1 -C 10 Alkyl, optionally substituted C 5 -C 10 Aryl, optionally substituted C 3 -C 10 Heteroaryl, optionally substituted C 3 -C 10 Cycloalkyl or optionally substituted C 3 -C 10 Heterocycloalkyl group. In some embodiments, R 8A Is hydrogen, hydroxy or optionally substituted C 1 -C 10 An alkyl group.
In some embodiments, the compounds useful in the present invention include compounds of formula IA wherein R 2A The method comprises the following steps:
in some embodiments, the compounds useful in the present invention include compounds of formula IA wherein R 2A Is an optionally substituted bicyclic ring or an optionally substituted fused ring. For example, in some embodiments, R 2A Selected from the group consisting of:
wherein R is 9A Is hydrogen, hydroxy, sulfonyl, optionally substituted C 1 -C 10 Alkyl, optionally substituted C 5 -C 10 Aryl, optionally substituted C 3 -C 10 Heteroaryl, optionally substituted C 3 -C 10 Cycloalkyl or optionally substituted C 3 -C 10 A heterocycloalkyl group.
In some embodiments, the compounds useful in the present invention include compounds of formula IA wherein R 2A The method comprises the following steps:
wherein R is 11a 、R 11b 、R 11c And R 11d Each of which is independently selected from hydrogen, hydroxy, sulfonyl, optionally substituted C 1 -C 10 Alkyl, optionally substituted C 5 -C 10 Aryl, optionally substituted C 3 -C 10 Heteroaryl, optionally substituted C 3 -C 10 Cycloalkyl or optionally substituted C 3 -C 10 A heterocycloalkyl group. In particular embodiments, R 2A The method comprises the following steps:
in some embodiments, the compounds used in the present invention are compounds of formula IA wherein each R a 、R b 、R c 、R d And R is e Selected from the group consisting of R a 、R b 、R c 、R d And R is e Any of the embodiments disclosed herein for each of; r is R 1A Selected from the group consisting of R 1A Any of the embodiments disclosed herein; and R is 2A Selected from the group consisting of R 2A Any of the embodiments disclosed herein.
In some embodiments, the compound used in the present invention is a compound selected from the group consisting of:
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
in some embodiments, the compound used in the present invention is a compound selected from the group consisting of:
In some embodiments, the compound used in the present invention is a compound of formula IIA or a pharmaceutically acceptable salt thereof:
substituent R of formula IIA f 、R g 、R h 、R i And R is j Each of which is independently selected from H, hydroxy, halogen, alkyl, alkoxy, CF 3 、SO 2 CH 3 And morpholino.
Substituent R of formula IIA 10A Is an optionally substituted cyclic amino group, and m A Is an integer from 0 to 3.
In some embodiments, the substitution of formula IIARadical R f 、R g 、R h 、R i And R is j Independently selected from the group consisting of H, hydroxy, and alkoxy. In some embodiments, substituent R of formula IIA f 、R g 、R h 、R i And R is j Independently selected from the group consisting of H, hydroxy, and methoxy. In some embodiments, substituent R f 、R g And R is j Each of (a) is independently H, and R g And R is h Independently selected from the group consisting of hydroxyl or methoxy.
In some embodiments, R of formula IIA 10A Is any of the optionally substituted aziridinyl, optionally substituted pyrrolidinyl, optionally substituted imidazolidinyl, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted oxopiperazinyl, or optionally substituted morpholinyl described above in relation to formula I, as well as substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted bicyclic, or substituted or unsubstituted fused rings alone.
In some embodiments, R of formula IIA 10A Are optionally substituted fused rings, such as:
wherein R is 11e 、R 11f 、R 11g And R 11h Each of which is independently selected from hydrogen, hydroxy, sulfonyl, optionally substituted C 1 -C 10 Alkyl, optionally substituted C 5 -C 10 Aryl, optionally substituted C 3 -C 10 Heteroaryl, optionally substituted C 3 -C 10 Cycloalkyl or optionally substituted C 3 -C 10 A heterocycloalkyl group. In certain embodiments, when m A When 2, R is 10A Not be
In some embodiments, R of formula IIA 10A The method comprises the following steps:
/>
/>
in some embodiments, the compounds used in the present invention are compounds of formula IIa:
substituent R of formula IIa k And R is l Each of which is independently selected from H, hydroxy, halogen, alkyl, alkoxy, CF 3 、SO 2 CH 3 And morpholino.
Substituent R of formula IIa 12A Selected from the group consisting of aryloxy, alkenyloxy, alkoxy, aminoalkyl, N-dimethylaminoalkyl, pyrrolidinyl, N-methylpyrrolidinyl, N-acylpyrrolidinyl, carboxyaminoalkyl, hydroxyalkyl, -O (CH) 2 ) 2 OC(O)CH 3 、 A group of groups.
In some embodiments, the substituent R of formula IIa k And R is l Independently selected from the group consisting of H, hydroxy, and methoxy. In some embodiments, R lA Is methoxy, and R k Is a hydroxyl group.
In some embodiments, the substituent R of formula IIa 12A Selected from the group consisting of phenyloxy, -OCH 2 CH＝CH 2 Methoxy, -CH 2 NH 2 、-CH(NH 2 )CH 3 、-CH 2 N(Me) 2 、-CH(CH 3 )N(Me) 2 、-CH 2 NHC(O)CH 3 、-CH(OH)CH 3 、-O(CH 2 ) 2 OC(O)CH 3 、/>A group of groups.
In some embodiments, the compound used in the present invention is a compound selected from the group consisting of:
/>
/>
in some embodiments, the compound used in the present invention is a compound selected from the group consisting of:
/>
/>
/>
additional embodiments include salts, solvates, stereoisomers, prodrugs and active metabolites of the compounds according to any of the embodiments described herein.
Some embodiments are directed to the free base form of a compound according to any of the embodiments described herein. Other embodiments include salts of such compounds (including, for example, pharmaceutically acceptable acid addition salts or pharmaceutically acceptable free base addition salts). Examples of pharmaceutically acceptable acid addition salts include, but are not limited to, salts derived from nitric acid, phosphoric acid, sulfuric acid, or hydrobromic acid, hydrochloric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and salts derived from non-toxic organic acids such as aliphatic monocarboxylic and aliphatic dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and acetic acid, maleic acid, succinic acid, or citric acid. Non-limiting examples of such salts include naphthalene disulfonate, benzenesulfonate, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, octanoate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like. Additional salt forms of the compounds described above include salts of amino acids (e.g., arginine salts, etc.) and gluconates, galacturonates (see, e.g., berge, et al, "Pharmaceutical Salts," j.pharma.sci.1977; 66:1).
Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines include N, N' -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine. Base addition salts of acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in a conventional manner. The free acid form may be regenerated by contacting the salt form with an acid and isolating the free acid.
Various embodiments include all salts and partial salts, i.e., salts having 1 equivalent, 2 equivalents, or 3 equivalents (preferably 2 equivalents) of base per mole of compound or acid of salt described above, salts having 1 equivalent, 2 equivalents, or 3 equivalents (preferably 1 equivalent) of acid per mole of base of compound according to any of the embodiments described herein. Generally, pharmaceutically acceptable salts of compounds according to any of the embodiments described herein can be readily prepared by appropriate use of the desired acid or base. The salt may be precipitated from the solution and collected by filtration, or may be recovered by evaporation of the solvent. For example, an aqueous solution of an acid (e.g., hydrochloric acid) may be added to an aqueous suspension of a compound according to any of the embodiments described herein, and the resulting mixture evaporated to dryness (lyophilized) to obtain the acid addition salt as a solid. Alternatively, a compound according to any of the embodiments described herein may be dissolved in a suitable solvent (e.g., an alcohol (such as isopropanol)), and the acid may be added in the same solvent or another suitable solvent. The resulting acid addition salt may then be precipitated directly or by addition of a less polar solvent such as diisopropyl ether or hexane and isolated by filtration.
Many organic compounds may form complexes with the solvent, with the organic compound being reacted in the solvent or precipitated or crystallized from the solvent. These complexes are referred to as "solvates". For example, a complex with water is known as a "hydrate". Various embodiments comprise solvates of the compounds according to any of the embodiments described herein. In some embodiments, salts of these compounds may form solvates.
Other embodiments include N-oxides of compounds according to any of the embodiments described herein. The N-oxide comprises an original unsubstituted sp 2 A heterocycle of N atom. Examples of such N-oxides include pyridyl N-oxide, pyrimidinyl N-oxide, pyrazinyl N-oxide, and pyrazolyl N-oxide.
The compounds according to any of the embodiments described herein may have one or more chiral centers and, depending on the nature of the individual substituents, may also have geometric isomers. Thus, embodiments include stereoisomers, diastereomers, and enantiomers of compounds according to any of the embodiments described herein. The chiral compounds may exist as individual enantiomers or as mixtures of enantiomers. Mixtures containing equal proportions of enantiomers are referred to as "racemic mixtures". Mixtures containing unequal parts of the enantiomer are described as having an "enantiomeric excess" (ee) of the R compound or S compound. The excess of one enantiomer in a mixture is usually described in terms of% enantiomeric excess. The ratio of enantiomers can also be defined by "optical purity" in which the degree to which a mixture of enantiomers rotates plane polarized light is compared to the individual optically pure R and S compounds. The compounds may also be substantially pure (+) or (-) enantiomers of the compounds described herein. In some embodiments, the composition may comprise substantially pure enantiomers, the substantially pure enantiomer being at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of one enantiomer. In certain embodiments, the composition may comprise a substantially pure enantiomer of at least 99.5% of one enantiomer.
The foregoing description includes all individual isomers of the compounds according to any of the embodiments described herein, and the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures thereof. Methods for determining the stereochemistry and resolution or stereotactic synthesis of stereoisomers are well known in the art. Diastereomers vary in both physical and chemical reactivity. Mixtures of diastereomers may be separated into pairs of enantiomers depending on solubility, fractional crystallization, or chromatographic properties (e.g., thin layer chromatography, column chromatography, or HPLC). Purification of a complex mixture of diastereomers to enantiomers usually requires two steps. In the first step, the mixture of diastereomers is resolved into pairs of enantiomers as described above. In a second step, the enantiomer pairs are further purified into a composition enriched in one or the other enantiomer, or more preferably resolved into a composition comprising the pure enantiomer. Resolution of enantiomers typically requires reaction or molecular interaction with chiral agents (e.g., solvents or column matrices). Resolution may be accomplished, for example, by converting a mixture of enantiomers (e.g., a racemic mixture) into a mixture of diastereomers by reaction with a pure enantiomer of the second agent (i.e., the resolving agent). The two resulting diastereoisomeric products may then be separated. The separated diastereomers are then reconverted to the pure enantiomers by reversing the initial chemical transformation.
Resolution of enantiomers may also be achieved by differences in non-covalent binding of the enantiomer to the chiral material (e.g., by chromatography on a pure chiral adsorbent). Non-covalent binding between the enantiomer and the chromatographic adsorbent forms a diastereomeric complex, resulting in differential partitioning in flow dynamics and bound states in the chromatographic system. Thus, the two enantiomers move through a chromatographic system (e.g., column) at different rates, allowing them to separate.
Further embodiments comprise prodrugs of compounds according to any of the embodiments described herein (i.e., compounds that release an active compound according to any of the embodiments described herein in vivo when administered to a mammalian subject). Prodrugs are pharmacologically active compounds or more generally inactive compounds that are converted to pharmacologically active agents by metabolic conversion. Prodrugs of compounds according to any of the embodiments described herein are prepared by modifying functional groups present in compounds according to any of the embodiments described herein in such a way that the modifications can be cleaved in vivo to release the parent compound. In vivo, prodrugs are susceptible to chemical changes (e.g., hydrolysis or action by naturally occurring enzyme (s)) under physiological conditions, resulting in release of the pharmacologically active agent. Prodrugs comprise compounds according to any of the embodiments described herein, wherein a hydroxyl group, amino group, or carboxyl group is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl group, amino group, or carboxyl group, respectively. Examples of prodrugs include, but are not limited to, esters of compounds according to any of the embodiments described herein (e.g., acetate derivatives, formate derivatives, and benzoate derivatives), or any other derivatives that will be converted to the active parent drug upon exposure to physiological pH or by enzymatic action. Conventional procedures for the selection and preparation of suitable prodrugs are described in the art (see, e.g., bundgaad. Design of procugs. Elsevier, 1985).
In some embodiments, one or more hydrogen atoms of a compound according to any of the embodiments described herein are replaced with deuterium. It was confirmed that deuteration of physiologically active compounds provides the advantage of retaining the pharmacological profile of their hydrogen counterparts (countpart) while positively affecting their metabolic results. Selective substitution of deuterium for one or more hydrogens in a compound according to any of the embodiments described herein may improve the safety, tolerability, and efficacy of the compound when compared to the full hydrogen counterparts of the compound.
Methods for incorporating deuterium into compounds have long been established. Using established metabolic studies in the art, compounds according to any of the embodiments described herein can be tested to identify sites for selective placement of deuterium isotopes, where the isotopes will not be metabolized. Furthermore, these studies identify metabolic sites as the locations where deuterium atoms will be placed.
Pharmaceutical compositions for use in the present invention
Some embodiments describe a pharmaceutical composition comprising: a compound according to any embodiment described herein, a pharmaceutically acceptable salt of a compound according to any embodiment described herein, a solvate of a compound according to any embodiment described herein, a stereoisomer of a compound according to any embodiment described herein, a prodrug of a compound according to any embodiment described herein, or an active metabolite of a compound according to any embodiment described herein; and a pharmaceutically acceptable carrier or diluent. The pharmaceutical compositions may be prepared in a manner well known in the pharmaceutical arts and may be administered by a variety of routes depending on whether local or systemic treatment is desired and depending on the area to be treated.
While it is possible that the compounds as described in any of the embodiments herein may be administered as bulk substances (bulk subtance), it is preferred to provide the compounds in a pharmaceutical formulation, for example, wherein the active agent is admixed with a pharmaceutically acceptable carrier selected according to the intended route of administration and standard pharmaceutical practice.
In particular, the present disclosure provides pharmaceutical compositions comprising a therapeutically effective amount of at least one compound according to any of the embodiments described herein and optionally a pharmaceutically acceptable carrier.
Combination of two or more kinds of materials
For the pharmaceutical compositions and methods of the present disclosure, compounds according to any of the embodiments described herein may be used in combination with other therapies and/or active agents.
In some embodiments, the rootThe compounds according to any of the embodiments described herein may be combined with one or more of anti-Vascular Endothelial Growth Factor (VEGF) treatment, vascular occlusion, and glaucoma treatment. In some embodiments, the compound is combined with a VEGF inhibitor selected from the group consisting of: bluoracer bead monoclonal antibodyNovartis, abelmoschusRegeron), ranibizumab (+.>Genentech), bevacizumab (++>Genentech) and pipatanib ( >Bausch+Lomb). In some embodiments, the compound is administered with a compound selected from the group consisting of verteporfin @Bausch+lomb) and laser therapy for vascular occlusion. In some embodiments, the compound is combined with complement cascade therapy selected from the group consisting of: POT-4 (+)>Alcon), ARC 1905 (Ophthotech), eculizumab (Eculizumab) (-) -on>Alexion Pharmaceuticals), FCFD4514S (Genntech), TA106 (Taligen Therapeutics and Alexion Pharmaceuticals), JSM-7717 (EvalutePharma), CR2-fH and C1INH (ViroPharma). In some embodiments, the compound is combined with a treatment for glaucoma selected from the group consisting of: brimonidine (+)>Allergan), apraclidine (apraclonidine)>Novartis), netal Shu Di (netarsudil) (-je ]>Aerie Pharmaceuticals). In some embodiments, the compound is combined with a treatment for glaucoma selected from the group consisting of beta blockers, carbonic anhydrase inhibitors, cholinergic agents (cholinergics) and prostaglandins.
In some embodiments, a compound according to any of the embodiments described herein may be combined with one or more of anti-Vascular Endothelial Growth Factor (VEGF) treatment, vascular occlusion, and glaucoma treatment. In some embodiments, the compound is combined with a VEGF inhibitor selected from the group consisting of: bluoracer bead monoclonal antibody Novartis, abelmoschusRegeron), ranibizumab (+.>Genentech), bevacizumab (++>Genentech) and pipatanib (>Bausch+Lomb). In some embodiments, the compound is administered with a compound selected from the group consisting of verteporfin @Bausch+lomb) and laser therapy for vascular occlusion. In some embodiments, the compounds and optionsCombination of complement cascade therapies from: POT-4 (+)>Alcon), ARC 1905 (Ophthotech), eculizumab (++>Alexion Pharmaceuticals), FCFD4514S (Genntech), TA106 (Taligen Therapeutics and Alexion Pharmaceuticals), JSM-7717 (EvalutePharma), CR2-fH and C1INH (ViroPharma). In some embodiments, the compound is combined with a treatment for glaucoma selected from the group consisting of: brimonidine (+)>Allergan), apracliding (/ -for)>Novartis), netuo Shu Di (/ -for)>Aerie Pharmaceuticals). In some embodiments, the compound is combined with a treatment for glaucoma selected from the group consisting of beta blockers, carbonic anhydrase inhibitors, cholinergic agents, and prostaglandins.
Thus, in a further aspect, the present disclosure provides a pharmaceutical composition comprising at least one compound according to any of the embodiments described herein, or a pharmaceutically acceptable derivative of a compound according to any of the embodiments described herein; a second active agent; and optionally a pharmaceutically acceptable carrier.
When combined in the same formulation, it will be understood that two or more compounds must be stable, and compatible with each other and with the other components of the formulation. When formulated separately, it may be provided in any convenient formulation in a manner known in the art for such compounds.
Preservatives, stabilizers, dyes and flavoring agents may be provided in any of the pharmaceutical compositions described herein. Examples of preservatives include sodium benzoate, ascorbic acid and esters of parahydroxybenzoic acid. Antioxidants and suspending agents may also be used.
With respect to combinations comprising biological products (e.g., monoclonal antibodies or fragments), suitable excipients will be employed to prevent aggregation or to stabilize the antibodies or fragments in solutions with low endotoxin that are typically used for parenteral administration (e.g., intravenous administration). See, for example, formulation and Delivery Issues for Monoclonal Antibody Therapeutics, daugherty et al in Current Trends in Monoclonal Antibody Development and Manufacturing, part 4,2010,Springer,New York pp 103-129.
The compounds according to any of the embodiments described herein may be milled using known milling procedures (e.g., wet milling) to obtain particle sizes suitable for tablet formation and other formulation types. Finely divided (nanoparticulate) formulations of the compounds can be prepared by methods known in the art (see, for example, WO 02/00196 (SmithKline Beecham)).
The compound according to any of the embodiments described herein, or a pharmaceutically acceptable salt of the compound according to any of the embodiments described herein, a solvate of the compound according to any of the embodiments described herein, a stereoisomer of the compound according to any of the embodiments described herein, a prodrug of the compound according to any of the embodiments described herein, or an active metabolite of the compound according to any of the embodiments described herein, may be formulated for any route of administration.
Route of administration and unit dosage form
Routes for administration (delivery) include, but are not limited to, one or more of the following: ocular topical administration (e.g., subconjunctival, intravitreal, retrobulbar, intracameral (intra-atrial)), oral administration (e.g., as a tablet, capsule, or as an absorbable solution), topical administration, mucosal administration (e.g., as a nasal spray or aerosol for inhalation), parenteral administration (e.g., by injectable form), gastrointestinal administration, intraspinal administration, intraperitoneal administration, intramuscular administration, intravenous administration, intraventricular administration, or other depot (delivery) administration, and the like.
Thus, a pharmaceutical composition according to any of the embodiments described herein comprises a pharmaceutical composition in a form specifically formulated for the mode of administration. In certain embodiments, the pharmaceutical compositions of the present disclosure are formulated in a form suitable for oral delivery. In some embodiments, the compound is an orally bioavailable compound suitable for oral delivery. In other embodiments, the pharmaceutical compositions of the present disclosure are formulated in a form suitable for parenteral delivery.
The compounds according to any of the embodiments described herein may be formulated for administration in any convenient manner for use in human or veterinary medicine, and thus the present disclosure includes within its scope pharmaceutical compositions comprising a compound according to any of the embodiments described herein suitable for use in human or veterinary medicine. Such pharmaceutical compositions may be used in conventional manner by means of one or more suitable carriers. Acceptable carriers for therapeutic applications are well known in the pharmaceutical arts and are described, for example, in Remington's Pharmaceutical Sciences, mack Publishing co. (a.r. gennaro kit.1985). The choice of drug carrier can be selected according to the intended route of administration and standard pharmaceutical practice. In addition to the carrier, the pharmaceutical composition may include any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), and/or solubilizing agent(s).
Depending on the delivery system, different pharmaceutical composition/formulation requirements may exist. It should be understood that not all non-compounds need be administered by the same route. Likewise, if the pharmaceutical composition comprises more than one active ingredient, those ingredients may be administered by different routes. For example, the pharmaceutical compositions of the present disclosure may be formulated for delivery by a topical ocular route, e.g., in subconjunctival ocular injection or intravitreal ocular injection, wherein the pharmaceutical composition is formulated for delivery by injection into the eye. Alternatively, the formulation may be designed for systemic administration, wherein the pharmaceutical composition is formulated for delivery by, for example, intravenous or oral route. Alternatively, the formulation may be designed to be delivered by a variety of routes.
The combination of a compound according to any of the embodiments described herein with an antibody or antibody fragment molecule may be formulated and administered by any of a number of routes and administered at a concentration that is therapeutically effective in the indication or for the purpose sought. To achieve this goal, antibodies can be formulated using a variety of acceptable excipients known in the art. Typically, the antibody is administered by injection (e.g., intravenous injection). Methods of achieving this administration are known to those of ordinary skill in the art. For example, gokarn et al, 2008,J Pharm Sci 97 (8): 3051-3066 (incorporated herein by reference) describe various high concentration antibody self-buffering formulations. For example, as known in the art, monoclonal antibodies in self-buffering formulations (e.g., 50mg/mL monoclonal antibody in 5.25% sorbitol (pH 5.0)), or 60mg/mL monoclonal antibody in 5% sorbitol, 0.01% polysorbate 20 (pH 5.2)) may be employed; or a conventional buffer formulation (e.g., 50mg/mL monoclonal antibody 1 (mAb 1) in 5.25% sorbitol, 25mM or 50mM acetate, glutamate or succinate (pH 5.0), or 60mg/mL in 10mM acetate or glutamate, 5.25% sorbitol, 0.01% polysorbate 20 (pH 5.2)); other lower concentration formulations.
Because some compounds of the present disclosure cross the blood-brain barrier, they can be administered in a variety of ways, including, for example, systemic methods (e.g., by intravenous (iv) route, subcutaneous injection (SC) route, oral route, mucosal route, transdermal route) or local methods (e.g., intracranial).
When a compound according to any of the embodiments described herein is administered directly to the eye, the compound may be administered topically to the eye or eyelid, for example using drops, ointments, creams, gels, suspensions, and the like. The compound(s) may be formulated with excipients such as methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, neutral poly (meth) acrylate, and other viscosity enhancing agents. The compound(s) may be injected into the eye, for example, subconjunctival or sub-tenon's injection, intravitreal injection, or retrobulbar injection. The compound(s) may be administered with a slow release drug delivery system such as a polymer, matrix, microcapsule or other delivery system formulated from, for example, glycolic acid, lactic acid, a combination of glycolic and lactic acids, liposomes, silicone, polyanliydide polyvinyl acetate alone or in combination with polyethylene glycol, and the like. The delivery device may be implanted in the eye (e.g., under the conjunctiva, in the wall of the eye, sutured to the sclera) for long-term drug delivery.
Pharmaceutically acceptable excipients and additives for ophthalmic use are known to those skilled in the art, (carriers, stabilizers, solubilizers, tonicity enhancing agents, buffer substances, preservatives, thickeners, complexing agents and other excipients). Examples of such additives and excipients can be found in U.S. Pat. nos. 5,891,913, 5,134,124 and 4,906,613. In some embodiments, the pharmaceutical compositions of the invention are prepared, for example, by mixing the active agents with corresponding excipients and/or additives to form corresponding ophthalmic compositions. The compounds according to any of the embodiments described herein may be administered in the form of eye drops, the active agent being conventionally dissolved in, for example, a carrier. The solution is adjusted and/or buffered to the desired pH, if appropriate, with the addition of stabilizers, solubilizers or tonicity enhancing agents. Preservatives and/or other excipients are added to the ophthalmic formulations of the present invention, as appropriate.
In the case of transmucosal delivery of a compound according to any of the embodiments described herein through the gastrointestinal mucosa, it should be able to remain stable during transport through the gastrointestinal tract; for example, it should be resistant to proteolytic degradation, stable at acidic pH values, and resistant to bile purification (subteneration) effects. For example, a compound according to any of the embodiments described herein that is prepared for oral administration may be coated with an enteric coating layer. The enteric coating layer material may be dispersed or dissolved in water or a suitable organic solvent. As enteric coating layer polymers, one or more of the following may be used alone or in combination: for example, a solution or dispersion of methacrylic acid copolymer, cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, cellulose acetate trimellitate, carboxymethyl ethylcellulose, shellac, or other suitable enteric coating layer polymer(s). In some embodiments, the aqueous enteric coating layer is a methacrylic acid copolymer.
The pharmaceutical compositions according to any of the embodiments described herein may be administered by inhalation, by use of a skin patch, orally (in the form of a tablet containing an excipient such as starch or lactose, or in the form of a capsule or ovule (ovule) alone or mixed with an excipient, or in the form of an elixir, solution or suspension containing a flavoring or coloring agent), or it may be injected parenterally (e.g., intravenously, intramuscularly, or subcutaneously). For buccal or sublingual administration, the pharmaceutical compositions according to any of the embodiments described herein may be administered in the form of tablets or lozenges, which may be formulated in a conventional manner.
In the case of parenteral administration of a pharmaceutical composition according to any of the embodiments described herein, such administration includes (but is not limited to): intravenous, intra-arterial, intrathecal, intraventricular, intracranial, intramuscular, or subcutaneous administration of a compound of the present disclosure; and/or by using infusion techniques. Antibodies or fragments are typically administered parenterally (e.g., intravenously).
Pharmaceutical compositions according to any of the embodiments described herein suitable for injection or infusion may be in the form of sterile aqueous solutions, dispersions or sterile powders which contain the active ingredient in such sterile solution or dispersion formulations which are adapted, if necessary, for infusion or injection. The formulation may optionally be encapsulated in liposomes. In all cases, the final formulation must be sterile, liquid and stable under both production and storage conditions. To improve storage stability, such formulations may also contain preservatives to prevent microbial growth. Prevention of the action of microorganisms can be achieved by adding various antibacterial and antifungal agents, for example, nipagin, chlorobutanol, or ascorbic acid (acid). In many cases isotonic substances (e.g. sugars, buffers and sodium chloride) are recommended to ensure an osmotic pressure similar to that of body fluids, in particular blood. Prolonged absorption of such injectable mixtures can be brought about by the introduction of an absorption delaying agent, such as aluminum monostearate or gelatin.
Dispersions can be prepared in liquid carriers or vehicles (e.g., glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof). The liquid carrier or vehicle may be a solvent or liquid dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, etc.), vegetable oils, non-toxic glycerides, and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the formation of liposomes, by the application of suitable particle sizes (in the case of dispersions), or by the addition of surfactants.
For parenteral administration, the compounds according to any of the embodiments described herein are preferably used in the form of a sterile aqueous solution which may contain other substances (e.g., sufficient salts or glucose) to make the solution isotonic with blood. If necessary, the aqueous solution should be suitably buffered (preferably to a pH of from 3 to 9). The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
Sterile injectable solutions may be prepared by mixing a compound according to any of the embodiments described herein with an appropriate solvent and one or more of the carriers described above, followed by sterile filtration. In the case of sterile powders which are suitable for use in the preparation of sterile injectable solutions, the preferred methods of preparation involve vacuum drying and freeze-drying which provides a powdered mixture of the compound with the desired excipient for the subsequent preparation of the sterile solution.
The compounds according to any of the embodiments described herein may be formulated for use in human or veterinary medicine by injection (e.g., by intravenous bolus or infusion or via intramuscular, subcutaneous or intrathecal route) and may be provided with added preservative(s), if necessary, in unit dosage form, in ampules or other unit dosage containers, or in multi-dose containers. The pharmaceutical composition for injection may be in the form of a suspension, solution or emulsion in an oily vehicle (vehicle) or an aqueous vehicle, and may contain a formulation such as a suspending agent, a stabilizing agent, a solubilizing agent and/or a dispersing agent. Alternatively, the active ingredient may be in the form of a sterile powder for reconstitution with a suitable vehicle (e.g., sterile pyrogen-free water) prior to use.
The compounds according to any of the embodiments described herein may be administered in the form of tablets, capsules, troches (troch), ovules, elixirs, solutions or suspensions, for quick release applications, delayed release applications, modified release applications, sustained release applications, pulsed release applications or controlled release applications.
The compounds according to any of the embodiments described herein may also be provided for human or veterinary use in a form suitable for oral or buccal administration (e.g., in the form of a solution, gel, syrup, or suspension, or dry powder for reconstitution with water or other suitable vehicle prior to use). Solid pharmaceutical compositions (e.g., tablets, capsules, lozenges, troches, pastilles (pastilles), pills, boluses (boluses), powders, pastes, granules, cartridges (bullets), or pre-mix formulations) may also be used. Solid and liquid pharmaceutical compositions for oral use can be prepared according to methods well known in the art. Such pharmaceutical compositions may also contain one or more pharmaceutically acceptable carriers and excipients, which may be in solid or liquid form.
Tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (preferably corn starch, potato starch or tapioca starch), sodium starch glycolate, croscarmellose sodium and certain complex silicates, and granulating binders such as polyvinylpyrrolidone, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), sucrose, gelatin and acacia.
In addition, lubricants (e.g., magnesium stearate, stearic acid, glyceryl behenate, and talc) may be included.
Pharmaceutical compositions according to any of the embodiments described herein may be administered orally in the form of fast-release or controlled-release tablets, microparticles, minitablets, capsules, sachets (sachets), as well as oral solutions or suspensions, or powders for their preparation. The oral formulation may optionally contain various standard pharmaceutical carriers and excipients (e.g., binders, fillers, buffers, lubricants, glidants, dyes, disintegrants, flavoring agents (odorants), sweeteners, surfactants, mold release agents, anti-adherents, and coatings). Some excipients may have a variety of roles in the pharmaceutical composition (e.g., as both a binder and a disintegrant).
Examples of pharmaceutically acceptable disintegrants for oral pharmaceutical compositions according to any of the embodiments described herein include, but are not limited to, starch, pregelatinized starch, sodium starch glycolate, sodium carboxymethyl cellulose, croscarmellose sodium, microcrystalline cellulose, alginates, resins, surfactants, effervescent compositions, aqueous aluminum silicate, and crosslinked polyvinylpyrrolidone.
Examples of pharmaceutically acceptable binders of oral pharmaceutical compositions according to any of the embodiments described herein include (but are not limited to) acacia; cellulose derivatives, such as methylcellulose, carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose or hydroxyethyl cellulose; gelatin, glucose, dextrose, xylitol, polymethacrylates, polyvinylpyrrolidone, sorbitol, starch, pregelatinized starch, tragacanth, xanthil resin, alginate, magnesium aluminum silicate, polyethylene glycol or bentonite.
Examples of pharmaceutically acceptable fillers for oral pharmaceutical compositions according to any of the embodiments described herein include, but are not limited to, lactose, dehydrated lactose, lactose monohydrate, sucrose, dextrose, mannitol, sorbitol, starch, cellulose (especially microcrystalline cellulose), monocalcium phosphate or anhydrous calcium phosphate, calcium carbonate, and calcium sulfate.
Examples of pharmaceutically acceptable lubricants useful in pharmaceutical compositions according to any of the embodiments described herein include, but are not limited to, magnesium stearate, talc, polyethylene glycol, polymers of ethylene oxide, sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearyl fumarate, and colloidal silica.
Examples of suitable pharmaceutically acceptable flavoring agents of the oral pharmaceutical compositions according to any of the embodiments described herein include, but are not limited to, synthetic flavors and natural flavor oils such as extracts of oils, flowers, fruits (e.g., banana, apple, tart cherry, peach), and combinations thereof and the like. The use of which depends on many factors, the most important being the organoleptic acceptability of the population to which the pharmaceutical composition is to be administered.
Examples of suitable pharmaceutically acceptable dyes for oral pharmaceutical compositions according to any of the embodiments described herein include, but are not limited to, synthetic dyes and natural dyes (such as titanium dioxide, beta-carotene, and naringin extract).
Examples of useful pharmaceutically acceptable coatings that are typically used to facilitate swallowing, alter release properties, improve appearance, and/or mask the taste of the pharmaceutical composition of oral pharmaceutical compositions according to any of the embodiments described herein include, but are not limited to, hydroxypropyl methylcellulose, hydroxypropyl cellulose, and acrylate-methacrylate copolymers.
Suitable examples of pharmaceutically acceptable sweeteners of the oral pharmaceutical composition according to any of the embodiments described herein include, but are not limited to, aspartame, saccharin, sodium cyclamate, xylitol, mannitol, sorbitol, lactose, and sucrose.
Suitable examples of pharmaceutically acceptable buffers include, but are not limited to, citric acid, sodium citrate, sodium bicarbonate, dibasic sodium phosphate, magnesium oxide, calcium carbonate, and magnesium hydroxide.
Suitable examples of pharmaceutically acceptable surfactants include, but are not limited to, sodium lauryl sulfate and polysorbates.
Solid compositions of a similar type may also be used as fillers in gelatin capsules. In view of this, preferred excipients include lactose, starch, cellulose, milk sugar (milk sugar) or high molecular weight polyethylene glycols. For aqueous suspensions and/or elixirs, the agents may be combined with various sweetening or flavouring agents, colouring matter or dyes, with emulsifying and/or suspending agents, and with diluents such as water, ethanol, polyethylene glycols and glycerin, and combinations thereof.
As shown, the compounds according to any of the embodiments described herein may be administered intranasally or by inhalation, and from pressurized containers, pumps, nebulizers or atomizers in the form of dry powder inhalants or aerosol sprays using suitable propellants (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane hydrofluoroalkanes (e.g., 1, 2-tetrafluoroethane (HFA 134 AT) or 1,2, 3-heptafluoropropane (HFA 227 EA)) carbon dioxide or other suitable gas) is conveniently delivered. In the case of pressurized aerosols, the dosage units may be determined by providing a raft to deliver a metered amount. The pressurized container, pump, nebulizer or atomizer may contain a solution or suspension of the active compound (e.g., using a mixture of ethanol and propellant as a solvent), which may additionally contain a lubricant (e.g., sorbitan trioleate).
Capsules and cartridges (e.g., made of gelatin) for use in an inhaler or insufflator may be formulated containing a powder mix of a compound according to any of the embodiments described herein and a suitable powder base such as lactose or starch.
For topical administration by inhalation, a compound according to any of the embodiments described herein may be delivered via a nebulizer for use in a human or veterinary drug.
The pharmaceutical compositions of the present disclosure may contain from 0.01% to 99% by weight of active material per volume. For topical application, for example, the pharmaceutical compositions will generally contain from 0.01 to 10% (more preferably from 0.01 to 1%) of the active material.
The compounds according to any of the embodiments described herein may also be administered in the form of liposome delivery systems (e.g., small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles). Liposomes can be formed from a variety of phospholipids (e.g., cholesterol, stearamide, or lecithin).
Pharmaceutical compositions or unit dosage forms according to any of the embodiments described herein may be administered according to dosages and administration regimens defined by conventional tests performed in view of the guidelines given above, in order to obtain optimal activity while minimizing toxicity or side effects for the particular patient. The dosage or unit dosage form of a compound can vary depending on a variety of factors (e.g., the underlying disease condition, the condition, weight, sex and age of the individual, and the mode of administration). The precise amount administered to a patient will vary depending on the state and severity of the disorder and the physical condition of the patient. Measurable improvements in any symptom or parameter can be determined by one skilled in the art or reported by the patient to a physician. It should be understood that any clinically or statistically significant reduction or improvement in any symptom or parameter is within the scope of the present disclosure. Clinically significant reductions or improvements mean to be perceptible to the patient and/or physician.
In some embodiments, the amount of the compound to be administered may be in the range of about 0.01 mg/kg/day and about 25 mg/kg/day. Typically, a dosage level of between 0.01mg/kg body weight and about 25mg/kg body weight is administered to a patient (e.g., a human) daily. In some embodiments, the therapeutically effective amount is at a lower limit of about 0.01mg/kg body weight, about 0.1mg/kg body weight, about 0.2mg/kg body weight, about 0.3mg/kg body weight, about 0.4mg/kg body weight, about 0.5mg/kg body weight, about 0.60mg/kg body weight, about 0.70mg/kg body weight, about 0.80mg/kg body weight, about 0.90mg/kg body weight, about 1mg/kg body weight, about 2.5mg/kg body weight, about 5mg/kg body weight, about 7.5mg/kg body weight, about 10mg/kg body weight, about 12.5mg/kg body weight, about 15mg/kg body weight, about 17.5mg/kg body weight, about 20mg/kg body weight, about 22.5mg/kg body weight, and about 25mg/kg body weight; and a upper limit of between about 25mg/kg body weight, about 22.5mg/kg body weight, about 20mg/kg body weight, about 17.5mg/kg body weight, about 15mg/kg body weight, about 12.5mg/kg body weight, about 10mg/kg body weight, about 7.5mg/kg body weight, about 5mg/kg body weight, about 2.5mg/kg body weight, about 1mg/kg body weight, about 0.9mg/kg body weight, about 0.8mg/kg body weight, about 0.7mg/kg body weight, about 0.6mg/kg body weight, about 0.5mg/kg body weight, about 0.4mg/kg body weight, about 0.3mg/kg body weight, about 0.2mg/kg body weight, about 0.1mg/kg body weight, and about 0.01mg/kg body weight. In some embodiments, the therapeutically effective amount is from about 0.1 mg/kg/day to about 10 mg/kg/day; in some embodiments, the therapeutically effective amount is about 0.2 mg/kg/day and about 5 mg/kg/day. It will be understood that the pharmaceutical formulations of the present disclosure need not necessarily contain the entire amount of the compound that is effective in treating a disorder, as such effective amounts can be achieved by administering multiple divided doses of such pharmaceutical formulations. The compounds may be administered according to a regimen of 1 to 4 times per day (e.g., once per day, twice per day, three times per day, or four times per day).
In some embodiments of the present disclosure, a compound according to any of the embodiments described herein is formulated into a capsule or tablet typically containing about 10mg to about 200mg of the compound. In some embodiments, the capsule or tablet contains about 10mg, about 15mg, about 20mg, about 25mg, about 30mg, about 35mg, about 40mg, about 45mg, about 50mg, about 55mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, about 105mg, about 110mg, about 115mg, about 120mg, about 125mg, about 130mg, about 135mg, about 140mg, about 145mg, about 150mg, about 155mg, about 160mg, about 165mg, about 170mg, about 175mg, about 180mg, about 185mg, about 190mg, about 195mg, about 200mg, about 195mg, about 190mg, about 185mg, about 180mg, about 175mg, about 170mg, about 165mg, about 160mg, about 155mg, about 150mg, about 145mg, about 140mg, about 135mg, about 130mg, about 125mg, about 115mg, about 15mg, about 40mg, about 45mg, about 50mg, about 45mg, about 35mg, about 15mg, about 50mg, about 45mg, about 35mg, about 15mg, about 50mg, about 15mg, about 45mg, about 50mg, about 15mg, about 50 mg.
In some embodiments, a compound according to any embodiment herein is administered to a patient at a total daily dose of 50mg to 500 mg. In some embodiments of the present invention, the daily dose is about 50mg, about 55mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, about 105mg, about 110mg, about 115mg, about 120mg, about 125mg, about 130mg, about 135mg, about 140mg, about 145mg, about 150mg, about 155mg, about 160mg, about 165mg, about 170mg, about 175mg, about 180mg, about 185mg, about 190mg, about 195mg, about 200mg, about 205mg, about 210mg, about 215mg, about 220mg, about 225mg, about 230mg, about 235mg, about 240mg, about 245mg, about 250mg, about 255mg, about about 260mg, about 265mg, about 270mg, about 275mg, about 280mg, about 285mg, about 290mg, about 295mg, 300mg, about 305mg, about 310mg, about 315mg, about 320mg, about 325mg, about 330mg, about 335mg, about 340mg, about 345mg, about 350mg, about 355mg, about 360mg, about 365mg, about 370mg, about 375mg, about 380mg, about 385mg, about 390mg, about 395, about 400mg, about 405mg, about 410mg, about 415mg, about 420mg, about 425mg, about 430mg, about 435mg, about 440mg, about 445mg, about 450mg, about 455mg, about 460mg, about 465mg about 260mg, about 265mg, about 270mg, about 275mg, about 280mg, about 285mg, about 290mg, about 295mg, 300mg, about 305mg, about 310mg, about 315mg, about 320mg, about 325mg, about 330mg, about 335mg, about 340mg, about 345mg, about 350mg, about 355mg, about 360mg, about about 365mg, about 370mg, about 375mg, about 380mg, about 385mg, about 390mg, about 395, about 400mg, about 405mg, about 410mg, about 415mg, about 420mg, about 425mg, about 430mg, about 435mg, about 440mg, about 445mg, about 450mg, about 455mg, about 460mg, about 465mg, about, about 120mg, about 115mg, about 110mg, about 105mg, about 100mg, about 95mg, about 90mg, about 85mg, about 80mg, about 75mg, about 70mg, about 65mg, about 60mg, about 55mg, and between the upper limits of about 50mg of a compound according to any embodiment herein. In some embodiments, the total daily dose is about 50mg to 150mg. In some embodiments, the total daily dose is about 50mg to 250mg. In some embodiments, the total daily dose is about 50mg to 350mg. In some embodiments, the total daily dose is about 50mg to 450mg. In some embodiments, the total daily dose is about 50mg.
Pharmaceutical compositions for parenteral administration contain from about 0.01% to about 100% by weight of the active compound according to any of the embodiments described herein, based on 100% by weight of the total pharmaceutical composition.
Generally, transdermal dosage forms contain from about 0.01% to about 100% by weight of the active compound according to any of the embodiments described herein, as compared to 100% total weight of the dosage form.
The pharmaceutical composition or unit dosage form may be administered in a single daily dose, or the total daily dose may be administered in divided doses. Furthermore, co-administration or sequential administration of additional compounds for the treatment of a disorder may be desirable. For this purpose, the combined active ingredients are formulated as individual dosage units.
In some embodiments, a compound according to any of the embodiments described herein generally inhibits aβ effects on neurons. In some embodiments, the compounds described above have an IC of less than about 100. Mu.M, about 50. Mu.M, about 20. Mu.M, about 15. Mu.M, about 10. Mu.M, about 5. Mu.M, about 1. Mu.M, about 500nM, about 100nM, about 50nM, or about 10nM with respect to inhibition of neurons (e.g., neurons in the brain), amyloid assembly or disruption thereof, and amyloid (including amyloid oligomers) binding and A.beta.action of amyloid deposition 50 . In some embodiments, a compound according to any of the embodiments described herein may have an IC of less than about 100 μm, about 50 μm, about 20 μm, about 15 μm, about 10 μm, about 5 μm, about 1 μm, about 500nM, about 100nM, about 50nM, or about 10nM with respect to inhibition of activity/effect of an aβ species (e.g., oligomer) on a neuron (e.g., central nervous system neuron) 50 。
Compounds according to any of the embodiments described herein may inhibit aβ action by specifically binding to the sigma-2 receptor. A compound may be considered "specific" for a sigma-2 receptor when it binds with a binding affinity that is at least 10% greater than the binding affinity to the sigma-1 receptor (even though the compound is capable of binding to both sigma-1 and sigma-2 receptors). Compounds of such embodiments may exhibit a specificity for sigma-2 receptor that is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, 500%, or 1000% greater than for sigma-1 receptor.
In some embodiments, the percent inhibition of one or more of the effects of aβ species (e.g., oligomers) on RPE and RGC (e.g., amyloid-induced oxidative stress, cell damage, cell death, and membrane transport abnormalities mediated by aβ oligomers) by a compound according to any of the embodiments described herein can be about 1% to about 20%, about 20% to about 50%, about 1% to about 50%, or about 1% to about 80% (as measured at a concentration from 10nM to 10 μm). Inhibition may be assessed, for example, by quantifying defects in Photoreceptor Outer Segment (POS) transport prior to exposure to the β -amyloid species and after exposure to the β -amyloid species, or in the presence of both a compound according to any of the embodiments described herein and an aβ species, wherein the compound according to any of the embodiments described herein occurs concurrently with, or prior to, or after, the aβ species exposure. As another example, inhibition may be assessed by determining membrane transport in the presence and absence of aβ species and in the presence and absence of compounds according to any of the embodiments described herein and comparing one or more parameters that measure the rate and extent of cellular aging or other indicators of cellular health and metabolism.
In some embodiments, an assay is used to determine whether a compound according to any of the embodiments described herein can bind to sigma-2 receptor. In some embodiments, the method further comprises determining whether a compound that binds to sigma-2 receptor acts as a functional antagonist at sigma-2 receptor by inhibiting soluble aβ oligomer-induced cytotoxicity.
Any form of beta-amyloid may be used in the practice of the screening methods and assays according to the present disclosure, including beta-amyloid monomers, oligomers, fibrils, and beta-amyloid associated with proteins ("protein complexes"), and more generally beta-amyloid assembly. For example, the screening method may employ various forms of soluble beta-amyloid oligomers (as disclosed, for example, in U.S. patent application serial No. 13/021,872, U.S. patent publication No. 2010/0240868, international patent application WO/2004/067561, international patent application WO/2010/01947, U.S. patent publication 20070098721, U.S. patent publication 20100209346, international patent application WO/2007/005359, U.S. patent publication 20080044356, U.S. patent publication 20070218491, WO/2007/126473, U.S. patent publication 20050074763, international patent application WO/2007/126473, international patent application WO/2009/048631, and U.S. patent publication 20080044406, U.S. patent No. 7,902,328, and U.S. patent No. 6,218,506, each of which is incorporated herein by reference).
The beta-amyloid form (comprising monomers or oligomers of beta-amyloid) may be obtained from any source. For example, in some embodiments, commercially available β -amyloid monomers and/or β -amyloid oligomers may be used in aqueous solution, and in other embodiments, the β -amyloid monomers and/or β -amyloid oligomers used in aqueous protein solution may be isolated and purified by a skilled artisan using any number of known techniques. In general, the β -amyloid monomers and/or β -amyloid oligomers used to prepare the aqueous solutions of the various real versions of proteins and β -amyloid may be soluble in the aqueous solution. Thus, both the protein and the β -amyloid protein of the aqueous solution may be soluble.
The added beta-amyloid may be of any isotype. For example, in some embodiments, the β -amyloid monomer may be β -amyloid 1-42, and in other embodiments, the β -amyloid monomer may be β -amyloid 1-40. In other embodiments, the beta-amyloid may be beta-amyloid 1-39 or beta-amyloid 1-41. Thus, the β -amyloid of various embodiments may comprise the C-terminal isoform of β -amyloid. Other embodiments comprise beta-amyloid in which the N-terminus has been worn, and in some embodiments, the N-terminus of any of the beta-amyloid C-terminal isoforms described above may be amino acids 2, 3, 4, 5, or 6. For example, beta-amyloid 1-42 may comprise beta-amyloid 2-42, beta-amyloid 3-42, beta-amyloid 4-42, or beta-amyloid 5-42, and mixtures thereof, and similarly beta-amyloid 1-40 may comprise beta-amyloid 2-40, beta-amyloid 3-40, beta-amyloid 4-40, or beta-amyloid 5-40.
The form of beta-amyloid used in the various embodiments may be wild-type (i.e., have an amino acid sequence identical to that of beta-amyloid synthesized in vivo by a majority of the population), or in some embodiments, the beta-amyloid may be a mutant beta-amyloid. Embodiments are not limited to any particular class of mutant β -amyloid. For example, in some embodiments, the β -amyloid introduced into the aqueous solution may comprise known mutations (such as, for example, β -amyloid with a "Dutch" mutation (E22Q) or a "north-polar" (E22G) mutation). These mutated monomers may comprise naturally occurring mutations (e.g., a β -amyloid form, a family form of β -amyloid isolated from a population of individuals susceptible to, for example, alzheimer's disease). In other embodiments, mutant β -amyloid monomers may be synthetically produced by using molecular techniques to produce β -amyloid mutants with specific mutations. In other embodiments, the mutant β -amyloid monomer may comprise mutants that have not been previously identified (such as, for example, those found in randomly generated β -amyloid mutants). As used herein, the term "β -amyloid" is intended to encompass any of the wild-type form of β -amyloid, as well as mutant forms of β -amyloid.
In some embodiments, the β -amyloid in the aqueous protein solution may be a single isoform. In other embodiments, the various C-terminal isoforms of β -amyloid and/or the various N-terminal isoforms of β -amyloid may be combined to form a β -amyloid mixture that may be provided in an aqueous protein solution. In other embodiments, the β -amyloid may be derived from Amyloid Precursor Protein (APP) that is added to an aqueous protein-containing solution and cleaved in situ, and in such embodiments, the solution may contain various isoforms of β -amyloid. After the β -amyloid has been added, N-terminal abrasion and/or removal of C-terminal amino acids may occur in aqueous solution. Thus, an aqueous solution prepared as described herein may contain multiple β -amyloid isoforms even when a single isoform is initially added to the solution.
The β -amyloid monomer added to the aqueous solution may be isolated from natural sources (e.g., living tissue), and in other embodiments, the β -amyloid may be derived from synthetic sources (e.g., transgenic mice or cultured cells). In some embodiments, the β -amyloid form (comprising monomers, oligomers, or combinations thereof) is isolated from normal subjects and/or patients that have been diagnosed with cognitive decline or a disease associated therewith, such as, but not limited to, alzheimer's disease. In some embodiments, the β -amyloid monomer, oligomer, or combination thereof is aβ assembly that has been isolated from a normal subject or a diseased patient. In some embodiments, aβ assembly is high molecular weight (e.g., greater than l00 KDa). In some embodiments, aβ assembly is medium molecular weight (e.g., 10KDa to l00 KDa). In some embodiments, aβ assembly is less than 10kDa.
The beta-amyloid oligomer of some embodiments may be composed of any number of beta-amyloid monomers, consistent with the usual definition of "oligomer". For example, in some embodiments, the beta-amyloid oligomer may comprise from about 2 to about 300, about 2 to about 250, about 2 to about 200 beta-amyloid monomers, and in other embodiments, the beta-amyloid oligomer may consist of about 2 to about 150, about 2 to about 100, about 2 to about 50, or about 2 to about 25 beta-amyloid monomers. In some embodiments, the beta-amyloid oligomer may comprise two or more monomers. The beta-amyloid oligomers of the various embodiments may be distinguished from beta-amyloid fibrils and beta-amyloid protofibrils based on the identity of the monomers. In particular, the β -amyloid monomers of the β -amyloid oligomer are typically spheres consisting of β -sheet sheets, while the secondary structure of the β -amyloid monomers of the fibrils and protofibrils are parallel β -sheets.
Provided herein is embodiment a method of treating dry age-related macular degeneration (dry AMD), comprising administering to a subject in need thereof a therapeutically effective amount of a compound selected from the group consisting of compounds of formula I,
Or a pharmaceutically acceptable salt thereof: wherein: r is R 1 And R is 2 Each of which is independently selected from H, C 1 -C 6 Alkyl, or CH 2 OR'; wherein if R is 1 And R is 2 R 'is present in each R' is independently H or C 1 -C 6 An alkyl group; r is R 3 、R 4 、R 5 And R 6 Independently selected from the group consisting of: H. c (C) 1 -C 6 Alkyl, OH, OCH 3 、OCH(CH 3 ) 2 、OCH 2 CH(CH 3 ) 2 、OC(CH 3 ) 3 、O(C 1 -C 6 Alkyl group, OCF 3 、OCH 2 CH 2 OH、O(C 1 -C 6 Alkyl) OH, O (C) 1 -C 6 Haloalkyl), F, cl, br, I, CF 3 、CN、NO 2 、NH 2 、C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Alkoxy C 1 -C 6 Alkyl, aryl, heteroaryl, C 3 -C 7 Cycloalkyl, heterocycloalkyl, alkylaryl, CO 2 R’、C(O)R’、NH(C 1 -C 4 Alkyl), N (C) 1 -C 4 Alkyl group 2 、NH(C 3 -C 7 Cycloalkyl), NHC (O) (C 1 -C 4 Alkyl), CONR' 2 、NC(O)R'、NS(O) n R'、S(O) n NR' 2 、S(O) n R'、C(O)O(C 1 -C 4 Alkyl), OC (O) N (R') 2 、C(O)(C 1 -C 4 Alkyl), and C (O) NH (C) 1 -C 4 An alkyl group); wherein if R is 3 、R 4 、R 5 And R 6 Wherein R 'is present, each R' is independently selected from the group consisting of: H. CH (CH) 3 、CH 2 CH 3 、C 3 -C 6 Alkyl, C 1 -C 6 Haloalkyl, or optionally substituted aryl, alkylaryl, piperazin-1-yl, piperidin-1-yl, morpholinyl, heterocycloalkyl, heteroaryl, C 1 -C 6 Alkoxy, NH (C) 1 -C 4 Alkyl), and N (C) 1 -C 4 Alkyl group 2 Wherein the optionally substituted group is selected from C 1 -C 6 Alkyl or C 2 -C 7 An acyl group; or R is 3 And R is 4 Forms, together with the C atom to which they are attached, a 4-membered, 5-membered, 6-membered, 7-membered or 8-membered cycloalkyl, aryl, heteroaryl or heterocycloalkyl group optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from: OH, amino, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl, or R 3 And R is 4 Are joined to form-O-C 1 -C 2 methylene-O-groups; or R is 4 And R is 5 Forms together with the C atom to which they are attached a 4-, 5-, 6-, or 6-membered ring,Cycloalkyl, aryl, heteroaryl or heterocycloalkyl groups of 7-or 8-membered optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from: OH, amino, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl, or R 4 And R is 5 Are joined to form-O-C 1-2 methylene-O-groups; r is R 7 、R 8 、R 9 、R 10 And R 11 Independently selected from the group consisting of: H. c (C) 1 -C 6 Alkyl, OH, OCH 3 、OCH(CH 3 ) 2 、OCH 2 CH(CH 3 ) 2 、OC(CH 3 ) 3 、O(C 1 -C 6 Alkyl group, OCF 3 、OCH 2 CH 2 OH、O(C 1 -C 6 Alkyl) OH, O (C) 1 -C 6 Haloalkyl), O (CO) R', F, cl, br, I, CF 3 、CN、NO 2 、NH 2 、C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Alkoxy C 1 -C 6 Alkyl, aryl, heteroaryl, C 3 -C 7 Cycloalkyl, heterocycloalkyl, alkylaryl, heteroaryl, CO 2 R’、C(O)R’、NH(C 1 -C 4 Alkyl), N (C) 1 -C 4 Alkyl group 2 、NH(C 3 -C 7 Cycloalkyl), NHC (O) (C 1 -C 4 Alkyl), CONR' 2 、NC(O)R'、NS(O) n R'、S(O) n NR' 2 、S(O) n R'、C(O)O(C 1 -C 4 Alkyl), OC (O) N (R') 2 、C(O)(C 1 -C 4 Alkyl), and C (O) NH (C) 1 -C 4 An alkyl group); wherein if R is 7 、R 8 、R 9 、R 10 And R 11 Wherein R 'is present, each R' is independently selected from the group consisting of: H. CH (CH) 3 、CH 2 CH 3 、C 3 -C 6 Alkyl group,C 1 -C 6 Haloalkyl, aryl, alkylaryl, piperazin-1-yl, piperidin-1-yl, morpholinyl, heterocycloalkyl, heteroaryl, C 1 -C 6 Alkoxy, NH (C) 1 -C 4 Alkyl), and N (C) 1 -C 4 Alkyl group 2 The method comprises the steps of carrying out a first treatment on the surface of the Or R is 7 And R is 8 Forms, together with the N or C atom to which they are attached, a 4-, 5-, 6-, 7-, or 8-membered cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from: OH, amino, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl, or R 7 And R is 8 Are joined to form-O-C 1-2 methylene-O-groups; or R is 8 And R is 9 Forms, together with the N or C atom to which they are attached, a 4-, 5-, 6-, 7-, or 8-membered cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from: OH, amino, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl, or R 8 And R is 9 Are joined to form-O-C 1-2 methylene-O-groups; each n is independently 0, 1, or 2; with the proviso that R 7 、R 8 、R 9 、R 10 And R 11 Not all H; and with the proviso that the following compounds or pharmaceutically acceptable salts thereof are excluded:
or alternatively.
Provided herein are embodiments B, methods of treating dry age-related macular degeneration (dry AMD), comprising administering to a subject in need thereof a therapeutically effective amount of a compound selected from the group consisting of compounds of formula IA:
or a pharmaceutically acceptable salt thereof: wherein: r is R a 、R b 、R c 、R d And R is e Independently selected from the group consisting of: H. hydroxy, cl, F, methyl, -OCH 3 、-OC(CH 3 ) 3 、O-CH(CH 3 ) 2 、CF 3 、SO 2 CH 3 And morpholino; r is R 1A Selected from the group consisting of: hydrogen, alkyl, phenyl, or-ch=c (CH 3 ) 2 The method comprises the steps of carrying out a first treatment on the surface of the And R is 2A Is an optionally substituted cyclic amino group.
In embodiment C, the method of embodiment a, wherein the compound is a compound of formula I or a pharmaceutically acceptable salt thereof.
In embodiment D, the method of any one of embodiments a to C, wherein the compound is:
or a pharmaceutically acceptable salt thereof.
In embodiment E, the method of any one of embodiments a to D, wherein the pharmaceutically acceptable salt is selected from the group consisting of: hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucarate, gluconate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate.
In embodiment F, the method of any one of embodiments a to E, wherein the pharmaceutically acceptable salt is a fumarate salt.
In embodiment G, the method of any one of embodiments a to F, wherein the compound is:
in embodiment H, the method of embodiment B, wherein the compound is a compound of formula IA or a pharmaceutically acceptable salt thereof.
In embodiment I, the method of one of embodiments A or H, wherein R 2A Is an optionally substituted piperidinyl group.
In embodiment J, the method of any of embodiments A, H or I, wherein R 2A Selected from the group consisting of:
in embodiment K, the method of any one of embodiments A, H, I or J, wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
Provided herein is embodiment L, a method of treating dry age-related macular degeneration (AMD), comprising administering to a subject in need thereof a therapeutically effective amount of a compound selected from the group consisting of:
/>
/>
in embodiment M, a method of treating dry age related macular degeneration, the method comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a compound according to any one of embodiments a-L and a pharmaceutically acceptable excipient.
In embodiment N, a method of treating dry age related macular degeneration, the method comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
in embodiment O, the method of embodiment N, wherein the pharmaceutically acceptable salt is selected from the group consisting of: hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucarate, gluconate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate.
In embodiment P, the method of embodiment N, wherein the pharmaceutically acceptable salt is a fumarate salt.
In embodiment Q, the method of embodiment P, wherein the compound is
Embodiment R is provided herein selected from The use of a compound of (c) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of dry age related macular degeneration.
Embodiment S is provided herein comprising a member selected from Use of a composition of a compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient in the manufacture of a medicament for the treatment of dry age-related macular degeneration.
In embodiment T, the use of a compound or composition of one of embodiments R or S, wherein the compound is a pharmaceutically acceptable salt thereof.
In embodiment U, the use of any one of embodiments R to T, wherein the pharmaceutically acceptable salt is selected from the group consisting of: hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucarate, gluconate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate.
In embodiment V, the use of embodiment U, wherein the pharmaceutically acceptable salt is fumarate.
In embodiment W, the use of one of embodiments R or S, wherein the compound is:
in embodiment X, the use of one of embodiments R or S, wherein the compound is:
in embodiment Y, the use of one of embodiments R or S, wherein the compound is:
in embodiment Z, the use of embodiment a to embodiment Y, wherein the compound is administered orally.
Examples
Aβ oligomer formulations are known to the person skilled in the art and can be found, for example, in WO2015/116923 and WO2018/213281, each of which is incorporated by reference in its entirety, which method constitutes another aspect of the present disclosure. The following sigma-2 receptor modulators are used in all examples:(Compound A); />
Example 1: test compounds for the treatment of dry AMD-related dysfunction
Experiment design:
cell culture: at 37℃and 5% CO 2 At the bottom, atHuman retinal pigment epithelial cell line ARPE19 purchased from ATCC was cultured in Ham's F-10 medium (Corning) supplemented with 10% Fetal Bovine Serum (FBS) and antibiotics (renewal medium every 48-72 hours). For all experimental purposes, cells were allowed to reach confluence (depending on the assay) in an appropriate culture vessel and then maintained in Ham's F-10 medium+5% FBS for 2 weeks prior to the experiment to ensure formation of fully polarized epithelial monolayers. Throughout the experiment, cells were visualized by an inverted microscope. The assay for detecting protective activity of ocular cells was performed according to Cai, h.et al, "High-Throughput Screening Identifies Compounds that Protect RPE Cells from Physiological Stressors Present in AMD," Exp Eye Res,185:10764 (2019), which is hereby incorporated by reference in its entirety.
Preparation of the compound: at 37℃and 5% CO 2 The compounds of the invention were added to the cell culture at a concentration of from 10nM to 10. Mu.M plus vehicle for pre-incubation for 24 hours.
Oxidative stress protocol: cultures pretreated with vehicle or compound of the invention are subjected to oxidative stress for 4 hours and 24 hours. In a second variant, ARPE-19 cells are treated with a compound of the invention for 24 hours before adding oxidative stressors or t-butylhydroperoxide (tBHP; 150 uM). Cell viability was assessed 24 hours after treatment via MTT assay, propidium Iodide (PI) staining, and/or Lactate Dehydrogenase (LDH) assay. The experimental protocol used in this study was: 1) vehicle without oxidative stressors (DMSO) -treated cells (healthy vehicle control), 2) vehicle with oxidative stressors (DMSO) -treated cells (damage control), 3) rescue control with oxidative stressors (e.g., nec-7) -treated cells (complete rescue of lesions + control).
Measurement and results:
cell viability assay: as previously described, the relative cell number is determined by absorption of crystal violet. Cells were washed 3 times in PBS, fixed in 4% paraformaldehyde in PBS, and stained in a solution of 0.1% crystal violet (Sigma Aldrich, C-3866), 10% ethanol. After washing 3 times in PBS, the remaining stain was dissolved in 10% acetic acid and absorbance was measured at 540nm with a microplate reader. Results: the compounds of the invention reduce the extent of cytotoxicity induced by oxidative stressors in a concentration-dependent manner
Measurement of oxidative damage: oxidative stress is an important factor in the development and acceleration of retinal diseases (e.g., macular degeneration) (Masuda T.et al., "Retinal Diseases Associated with Oxidative Stress and the Effects of a Free Radical Scavenger," Oxidative Medicine and Cellular Longevity Vol.2017, article ID 9208489, (2017); and Forest, D.L., et al., "Cellular Models and Therapies for Age-Related Macular Degeneration," Dis Model Mech 8 (5): 421-427 (2015); which is incorporated herein by reference in its entirety). Oxidative damage was measured by: 1) Human 4HNE (4-hydroxynonenoic acid) ELISA (enzyme linked immunosorbent assay) kit for lipid peroxidation and 2) protein carbonyl assay to detect oxidative damage of proteins. Results: the compounds of the present invention reduce the extent of oxidative damage induced by oxidative stressors in a concentration-dependent manner as measured by reduced lipid peroxidation and reduced formation of protein carbonyl groups.
Measurement of reactive oxygen species: cells were harvested and incubated in PBS containing 10mM CM-H2DCFDA (chloromethyl derivative of 2',7' -dichlorofluorescein diacetate; life Technologies, D-399) for 30min at 37℃in the dark to allow dye loading into the cells. The dye is non-fluorescent upon chemical reduction, and becomes fluorescent upon cell oxidation and cell esterase removal of acetate groups. The production of reactive oxygen species within the cell was monitored by flow cytometry with excitation at 480nm and emission at 530 nm. Results: the compounds of the invention reduce the formation of reactive oxygen species induced by oxidative stressors in a concentration dependent manner as measured by reduced CM-H2DCFDA fluorescence.
Mitochondrial membrane potential (Δψm): cationic fluorescent tetramethyl rhodamine (TMRM) dye (Thermo Scientific) determines Δψm, which accumulates particularly in the bioenergy-active mitochondria. The dye diffuses out from the mitochondria with lower membrane potential. ARPE19 cells were loaded with TMRM (50 nM) at 37℃for 30 min, prior to the end of treatment, with pancreatic proteinsThe enzyme was used and the particles were resuspended in PBS and immediately evaluated by flow cytometry (excitation/emission: 510/580 nm). UsingThe software analyzes the data. M-chlorophenyl hydrazone CCCP was added as a positive control. Results: the compounds of the invention prevent changes in mitochondrial membrane potential induced by oxidative stressors in a concentration-dependent manner as measured by TMRM fluorescence.
Mitochondrial mass and function assays: the estimate of mitochondrial mass was measured by loading ARPE-19 cells with MitoTracker Green (excitation/emission: 490/516 nM) at a final concentration of 100nM (37 ℃,15 min). Cells were washed with PBS and collected after trypsinization with 0.05% trypsin. Analysis of each treatment 1×10 using flow cytometry 4 Individual cells were used for MitoTracker fluorescence intensity. Mitochondrial function was measured using the MTT assay kit and cell viability data were normalized to account for any cell death or proliferation. Results: the compounds of the invention prevented changes in mitochondrial mass and function induced by oxidative stressors in a concentration dependent manner as measured by MitoTracker Green fluorescence and MTT assays.
Autophagy flux assay: cells were lysed in RIPA buffer (radioimmunoprecipitation assay buffer, thermo Scientific, 89901) containing protease inhibitors (Roche Applied Science, 11873580001). Cell lysates containing equal amounts of protein were re-loaded into individual wells and separated on a 12% SDS-PAGE gel (sodium dodecyl sulfate-polyacrylamide gel electrophoresis gel). After separation, the proteins were transferred to nitrocellulose membranes (0.22 mm; bio-Rad Laboratories, 162-0112) and non-specific binding sites were blocked by treatment with 5% skim milk powder (Fisher Scientific, NC 0339922) or Licor fixation buffer (Li-Cor Biosciences, 927-40000). The membrane was then incubated with primary antibodies to LC3B (1:1000), ATG7 (1:1000), or ATG9 (1:1000). The primary antibody treatment was followed by treatment with horseradish peroxidase conjugated secondary antibodies (for ECL detection system) or secondary infrared dye-800 conjugated anti-rabbit dye or Alexa Fluor 680 conjugated anti-mouse IgG (for Licor Odyssey system) at room temperature for 1 hour. To determine the equivalent protein loading, the blots were probed again with anti-ACTB (anti- β -actin) antibodies (1:5000 dilution) or a-tubulin antibodies (1:5000 dilution). For band detection, the membranes were incubated with a Western blot detection system (ECL Plus) and exposed to single layer emulsion film (Biomax MR Sigma, Z370398-50 EA). The band intensities were determined using software developed by Wayne Rasband (ImageJ; national institutes of health, bethesda, MD; available from http:// rsb.info. Gov/ij/index. Html). Statistical significance was calculated using the Mann-Whitney U-test. LC3-II ratio LC3-I determines autophagy flux. Autophagosomes were also detected by immunostaining. After completion of the respective treatments, the cells were washed 2 times in PBS and fixed in 4% paraformaldehyde for 15 minutes, and then autophagy spots were immunostained using rabbit polyclonal LC3 antibody (Novus Biologicals, NB 100-2220). Fluorescent micrographs of immunostained LC3 were obtained and analyzed by Axiovision Rel 4.4 software (Zeiss, oberkochen, germany). Punctate staining of LC3 formed after oxidative stress indicates autophagosome formation. Results: the compounds of the invention normalize the changes in autophagy flux induced by oxidative stressors in a concentration dependent manner as measured by western blot analysis and immunostaining of LC3B, ATG7 and ATG 9.
Cell death assay: cell death is a key feature of dry AMD (Yang, m., et al, "Novel Programmed Cell Death as Therapeutic Targets in Age-Related Macular Degeneration," int.j.mol.sci.,21 (19): 7279 (2020), which is hereby incorporated by reference in its entirety). Functional cell-based assays were performed in retinal pigment epithelial cells (RPE)) to assess cell viability following oxidative stress (triggering of cell death). The data indicate that sigma-2 receptor modulators rescue cell death triggered by oxidative stress in a concentration-dependent manner (FIGS. 1A and 1B)
Determination of lysosomal integrity and activity: retinal pigment epithelial cells were plated into 8-well cover glass bottom chambers (Lab-Tek, naperville, IL) and cells were incubated in 1mg/ml of the pH indicator Lysosensor Yellow/Blue dextran (Molecular Probes, eugene, OR) for 12 hours in the presence OR absence of different oxidative stressors. The labeled cells were observed using a laser scanning confocal microscope (using excitation at 360nm and emission at 450nm and long-pass emission at 515 nm). A higher 530/450nm ratio (i.e. turning green) correlates to a lower pH. Cathepsin D activity in cell lysates was measured using a fluorometric cathepsin D activity assay kit (Abcam, cambridge, MA) and values are presented in relative fluorescence units per million cells. Results: the compounds of the invention prevent loss of lysosomal integrity and activity induced by oxidative stressors in a concentration-dependent manner as measured by LysoSensor yellow/blue fluorescence assays.
Example 2: in vitro model of retinal pigment epithelial cells
Naturally occurring Retinal Pigment Epithelial (RPE) cells, such as ARPE-19 cells, are cultured as described in example 1. Briefly, aged cells grown on transwell inserts that allow mature pigmented RPE monolayer cells to mimic several aspects (ultrastructural, physiological, and functional) of in situ/ocular RPE cells were used in experiments to test the efficacy of the compounds of the invention in preventing or treating cellular dysfunction.
Human pluripotent stem cell (iPSC) -derived RPE lines are highly characterized and are considered mature pigmented monolayer cells with intact barrier function and RPE physiological function (e.g., vascular Endothelial Growth Factor (VEGF) secretion), and are used to test the efficacy of the compounds of the invention in preventing or treating cellular dysfunction.
Primary RPE cells from healthy and AMD donors are the most physiologically and pathophysiologically relevant cell models for studying AMD-associated phenotypes and functions and are used in experiments to test the efficacy of the compounds of the invention in preventing or treating cellular dysfunction.
Example 3: in vitro modulation of important pathways in dry AMD
Proof of concept studies suggest a clear role for sigma-2 receptor modulators in the key aspect of rescue of dry AMD. Mechanism studies and pathway analysis in disease-related assays indicate a key role for sigma-2 receptor modulators in dry AMD as studied in RPE cells.
Oxidative stress: oxidative stress is a critical aspect of AMD, and oxidative damage results in defects in Photoreceptor Outer Segment (POS) transport in RPE cells, which causes accumulation of toxic macromolecules and disruption of autophagy-lysosomal pathways and cellular protein homeostasis. Hydrogen peroxide (H) 2 O 2 ) Is the medium of oxidative stress in the human vitreous and is therefore used for RPE monolayers. The RPE monolayers were exposed to different concentrations of oxidative stress to mimic the oxidative stress present in AMD and aged retinas. Cultures were pretreated with oxidative stressors and evaluated for their ability to transport and break down fluorescently labeled POS, including measuring late compartments critical to material degradation (cargo degradation), such as lysosomes and autophagosomes. Cells are tested in the presence or absence of a compound of the invention. The compounds of the invention reduce the extent of oxidative damage induced by oxidative stressors in a concentration-dependent manner.
Complement inhibition: complement dysregulation is a major contributor genetically related to about half of AMD cases. Complement C3 is a key upstream component of the complement cascade. In donor RPE cells of AMD patients carrying complement factor H Y402H polymorphism, C3 turnover was significantly increased, resulting in higher internalization and deposition of terminal complex C5b-9 in lysosomes. Studies of RPE cells in Stokes' disease (Stargardt disease), which are similar to AMD, revealed increased endosomes that transport C3. To mimic complement dysregulation in vitro, we aimed at complement C3 activity. The cultured RPE cells were exposed to cobra venom to reproduce disruption of the complement pathway by targeting C3. In this model, CD59 recycling and lysosomal extracellular secretion following complement attack are defective and do not protect RPE cells. Evidence suggests that complement imbalance disrupts substance transport and processing in the RPE (cargo trafficking and processing). In this model, the culture is exposed to snake venom, and then the Photoreceptor Outer Segment (POS) is added to the medium in the presence or absence of the compound, and the extent of rescue is determined. Chatelet DS: study of Intracellular Cargo Trafficking and Co-localization in the Phagosome and Autophagy-Lysosomal Pathways of Retinal Pigment Epithelium (RPE) cells.methods Mol Biol 2020, according to Ratnayaka JA, keeling E; 2150:167-82 outer photoreceptor segments were prepared. The compounds of the invention can rescue cell death of the RPE barrier and defects in transepithelial electrical resistance (TEER).
Aβ oligomer exposure: aβ mediates pathogenesis in RPE cells characterized by defects in photoreceptor outer segment transport, barrier (tight junction) integrity and cell health. RPE cultures were treated with human oligomeric aβ in the presence or absence of the compounds of the invention. The integrity of the POS transport and barrier is measured by assays and the health of the cells is determined with Lactate Dehydrogenase (LDH). The compounds of the invention can rescue defects in photoreceptor outer segment transport, barrier integrity and cell health triggered by oligomeric aβ.
Autophagy assay: according to Klionsky et al, "Guidelines for the Use and Interpretation of Assays for Monitoring Autophagy," (4 th edition)Autophagy2021; autophagy assays were performed at 17:1-382 (which is hereby incorporated by reference in its entirety). RPE cultures were treated with human oligomeric aβ in the presence or absence of the compounds of the invention. POS transport was measured over time after POS addition to RPE cell cultures. Stressors comprising Abeta oligomers or H for 12 to 48 hours 2 O 2 Is added to the system. These studies indicate that POS will be transported over time at a normal rate after addition of POS to RPE cell cultures. This process is disrupted after addition of stressors such as aβ oligomers (fig. 2A and 2B) or oxidative stress (fig. 3A and 3B). The presence of sigma-2 receptor modulators (compound a and compound C) restored normal transport following autophagosome stress as measured by co-localization of POS with microtubule-associated protein 1 light chain 3B (LC 3B) following stress (fig. 2A and 2B and fig. 3A and 3B).
Oxidative stressors are associated with the pathology of AMD in which autophagy-related proteins are altered. Application of oxidative stressors caused a dramatic increase in the expression of autophagy-related proteins (fig. 4). Sigma-2 receptor modulator compound a and compound C prevented this increase in autophagy-related proteins (fig. 4).
EXAMPLE 4 prevention of aging of retinal pigment epithelial cells
Experiment design: primary RPE cultures or ARPE-19 cells 6 to 10 were treated with non-lethal CSCs (cigarette smoke condensate; 150 uM) to cause RPE cell senescence in the presence or absence of the compounds of the invention. Cell senescence was assessed by b-galactosidase immunocytochemistry 6 to 10 days after treatment. Experimental control: 1) CSC-free vehicle (DMSO) -treated cells (healthy vehicle control), 2) vehicle-treated cells (senescence + control) that are CSC-treated (DMSO), 3) rescue + control (e.g., mitochondrial DRP1 mutant protein with CSC-treated virus-treated cells) (partial rescue of senescence + control). Experimental results: the compounds of the invention prevent aging of RPE cells triggered by CSC administration.
Example 5 prevention of inflammatory response in retinal pigment epithelial cells
Experimental design THP-1 cells were treated with medium from cultured RPE cells that underwent oxidative stress to induce expression of pro-inflammatory markers in THP-1 cells. Prior to THP-1 cell treatment, RPE cells were treated with the compounds of the invention (+/-oxidative stress) to prevent pro-inflammatory responses in THP-1 cells. Experimental control: 1) Vehicle (DMSO) -treated cells (healthy vehicle control), 2) vehicle (DMSO) -treated RPE-derived medium (thp+ control). Experimental results: the compounds of the invention prevent a pro-inflammatory response in THP cells triggered by the administration of RPE derived medium.
EXAMPLE 6 prevention of apoptosis of retinal ganglion cells
Experiment design: in the optic nerve compression model, immunized Retinal Ganglion Cells (RGCs) are cultured with an elevated concentration of a compound described herein. Caspase 3 activity and cell viability in retinal ganglion cells was assessed by calcein-AM staining. Experimental results: the compounds of the invention prevent apoptosis of retinal ganglion cells.
Example 7 prevention of ocular hypertension
Experiment design: the rise in intraocular pressure in rats is induced by applying light from a diode laser onto the trabecular meshwork, with or without the compound of the invention. Axons in the optic nerve were counted 24 hours after ocular hypertension was induced. Experimental results: the compounds of the invention prevent ocular high pressure induced cell death and prevent axonal damage induced functional defects.
Example 8: in vivo penetration of the retina
The compounds of the invention administered orally at concentrations exceeding 80% occupancy of sigma-2 receptors penetrate the retina.
Following a single oral administration of [14C ] -Compound A to rats, autoradiography was performed to determine tissue distribution. Throughout the course of 24 hours, concentrations of [14C ] -compound a were found to exceed 80% receptor occupancy at sigma-2 receptors in the uveal/retinal membrane and these concentrations were comparable to the concentrations in the brain (fig. 5). In vivo receptor occupancy in excess of 80% may produce efficacy. Drug concentrations in the brain (cerebellum), retina and plasma were also measured. Throughout the 24 hour period, the concentration in the retina exceeded 80% receptor occupancy at sigma-2 receptors and was higher than in the brain or plasma (fig. 6). Similarly, following a single oral administration dose, compound B concentration was found to exceed 80% receptor occupancy at sigma-2 receptors in retina and plasma and approximately 50% occupancy in brain (fig. 7).
Example 9: sigma-2 receptor modulators in glaucoma
The utility of sigma-2 receptor modulators was tested using an in vivo model of glaucoma (Shah, m., et al, "Translational Preclinical Pharmacologic Disease Models for Opthalmic Drug Development," development.pharm.res.36 (4): 58 (2019); which is hereby incorporated by reference in its entirety).
To test whether sigma-2 receptor modulators can rescue cell death, in vivo models were used to cause cell death of retinal ganglion cells, similar to that seen in patients with glaucoma and other retinal diseases. Like the baseline positive control, the addition of sigma-2 receptor modulator compound B significantly protected retinal ganglion cell counts (p < 0.05) (fig. 8).
Glaucoma can cause disturbances in the electrical activity of the retina. To measure electrical activity, a Pattern Electroretinogram (PERG) measures the electrical activity of the retina in response to a test stimulus (e.g., reversing the checkerboard). PERG is a non-invasive, direct and objective method of assessing retinal ganglion cell function. In vivo models of glaucoma cause functional defects (damaged and primitive) in retinal ganglion cells, similar to what is seen in patients with glaucoma and other retinal diseases. Sigma-2 receptor modulator compound A protects retinal ganglion cell function (FIGS. 9A and 9B; P < 0.05).
Example 10: disease indication
An unbiased pathway analysis of proteomic data obtained during clinical trials provided evidence of the relationship between sigma-2 receptor complex and dry AMD. Cerebrospinal fluid (CSF) is analyzed to determine which pre-designated functional disease entities may be affected by the administration of compound a. These analyses confirm that geographic atrophy and macular degeneration are the two most prominent indications affected (table 2). Subsequent analysis confirmed several subsets of the proteins altered by compound a, which were involved in dry AMD.
Table 2: top grade disease body
In the subsequent analysis, the overlap of altered proteins in CSF and plasma biofluids of AD patients treated with compound a with placebo was examined, confirming a group of altered proteins by compound a. Other groups have shown that these proteins are destroyed in dry AMD or geographic atrophy compared to age-matched controls. Subsequent analysis confirms several pathways in which these proteins are involved, many of which are known to be genetically or biologically linked to the process of disruption in dry AMD. The comprehensive insight provided by these assays provides evidence of early concepts that sigma-2 receptor modulators are able to alter AMD-related proteins and pathways in the elderly patient population.
Synthetic examples
Compounds according to any of the embodiments described herein may be prepared by general and specific methods outlined in, for example, WO2013/029057, WO2015/116923 and WO2018/213281 (each of which is incorporated by reference in its entirety), which methods constitute another aspect of the present disclosure.

Claims (25)

1. A method of treating dry age-related macular degeneration (dry AMD), the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound selected from the group consisting of:
a: the compound of the formula I is a compound of formula I,
or a pharmaceutically acceptable salt thereof:
wherein:
R 1 and R is 2 Each of which is independently selected from H, C 1 -C 6 Alkyl, or CH 2 OR'; wherein if R is 1 And R is 2 R 'is present in each R' is independently H or C 1 -C 6 An alkyl group;
R 3 、R 4 、R 5 and R 6 Independently selected from the group consisting of: H. c (C) 1 -C 6 Alkyl, OH,OCH 3 、OCH(CH 3 ) 2 、OCH 2 CH(CH 3 ) 2 、OC(CH 3 ) 3 、O(C 1 -C 6 Alkyl group, OCF 3 、OCH 2 CH 2 OH、O(C 1 -C 6 Alkyl) OH, O (C) 1 -C 6 Haloalkyl), F, cl, br, I, CF 3 、CN、NO 2 、NH 2 、C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Alkoxy C 1 -C 6 Alkyl, aryl, heteroaryl, C 3 -C 7 Cycloalkyl, heterocycloalkyl, alkylaryl, CO 2 R’、C(O)R’、NH(C 1 -C 4 Alkyl), N (C) 1 -C 4 Alkyl group 2 、NH(C 3 -C 7 Cycloalkyl), NHC (O) (C 1 -C 4 Alkyl), CONR' 2 、NC(O)R'、NS(O) n R'、S(O) n NR' 2 、S(O) n R'、C(O)O(C 1 -C 4 Alkyl), OC (O) N (R') 2 、C(O)(C 1 -C 4 Alkyl), and C (O) NH (C) 1 -C 4 An alkyl group); wherein if R is 3 、R 4 、R 5 And R 6 Wherein R 'is present, each R' is independently selected from the group consisting of: H. CH (CH) 3 、CH 2 CH 3 、C 3 -C 6 Alkyl, C 1 -C 6 Haloalkyl, or optionally substituted aryl, alkylaryl, piperazin-1-yl, piperidin-1-yl, morpholinyl, heterocycloalkyl, heteroaryl, C 1 -C 6 Alkoxy, NH (C) 1 -C 4 Alkyl), and N (C) 1 -C 4 Alkyl group 2 Wherein the optionally substituted group is selected from C 1 -C 6 Alkyl or C 2 -C 7 An acyl group;
or R is 3 And R is 4 Forms, together with the C atom to which they are attached, a 4-membered, 5-membered, 6-membered, 7-membered or 8-membered cycloalkyl, aryl, heteroaryl or heterocycloalkyl group optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from: OH, amino, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl, or R 3 And R is 4 Are joined to form-O-C 1 -C 2 methylene-O-groups;
or R is 4 And R is 5 Forms, together with the C atom to which they are attached, a 4-membered, 5-membered, 6-membered, 7-membered or 8-membered cycloalkyl, aryl, heteroaryl or heterocycloalkyl group optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from: OH, amino, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl, or R 4 And R is 5 Are joined to form-O-C 1-2 methylene-O-groups;
R 7 、R 8 、R 9 、R 10 and R 11 Independently selected from the group consisting of: H. c (C) 1 -C 6 Alkyl, OH, OCH 3 、OCH(CH 3 ) 2 、OCH 2 CH(CH 3 ) 2 、OC(CH 3 ) 3 、O(C 1 -C 6 Alkyl group, OCF 3 、OCH 2 CH 2 OH、O(C 1 -C 6 Alkyl) OH, O (C) 1 -C 6 Haloalkyl), O (CO) R', F, cl, br, I, CF 3 、CN、NO 2 、NH 2 、C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Alkoxy C 1 -C 6 Alkyl, aryl, heteroaryl, C 3 -C 7 Cycloalkyl, heterocycloalkyl, alkylaryl, heteroaryl, CO 2 R’、C(O)R’、NH(C 1 -C 4 Alkyl), N (C) 1 -C 4 Alkyl group 2 、NH(C 3 -C 7 Cycloalkyl), NHC (O) (C 1 -C 4 Alkyl), CONR' 2 、NC(O)R'、NS(O) n R'、S(O) n NR' 2 、S(O) n R'、C(O)O(C 1 -C 4 Alkyl), OC (O) N (R') 2 、C(O)(C 1 -C 4 Alkyl), and C (O) NH (C) 1 -C 4 An alkyl group); wherein if R is 7 、R 8 、R 9 、R 10 And R 11 Wherein R 'is present, each R' is independently selected from the group consisting of: H. CH (CH) 3 、CH 2 CH 3 、C 3 -C 6 Alkyl, C 1 -C 6 Haloalkyl, aryl, alkylaryl, piperazin-1-yl, piperidin-1-yl, morpholinyl, heterocycloalkyl, heteroaryl, C 1 -C 6 Alkoxy, NH (C) 1 -C 4 Alkyl), and N (C) 1 -C 4 Alkyl group 2 ；
Or R is 7 And R is 8 Forms, together with the N or C atom to which they are attached, a 4-, 5-, 6-, 7-, or 8-membered cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from: OH, amino, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl, or R 7 And R is 8 Are joined to form-O-C 1-2 methylene-O-groups;
or R is 8 And R is 9 Forms, together with the N or C atom to which they are attached, a 4-, 5-, 6-, 7-, or 8-membered cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from: OH, amino, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl, or R 8 And R is 9 Are joined to form-O-C 1-2 methylene-O-groups;
each n is independently 0, 1, or 2;
with the proviso that R 7 、R 8 、R 9 、R 10 And R 11 Not all H; and is also provided with
With the proviso that the following compounds or pharmaceutically acceptable salts thereof are excluded:
or alternatively
B: compounds of formula IA
Or a pharmaceutically acceptable salt thereof:
wherein:
R a 、R b 、R c 、R d and R is e Independently selected from the group consisting of: H. hydroxy, cl, F, methyl, -OCH 3 、-OC(CH 3 ) 3 、O-CH(CH 3 ) 2 、CF 3 、SO 2 CH 3 And morpholino;
R 1A selected from the group consisting of: hydrogen, alkyl, phenyl, or-ch=c (CH 3 ) 2 The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with
R 2A Is an optionally substituted cyclic amino group.
2. The method of claim 1, wherein the compound is a compound of formula I or a pharmaceutically acceptable salt thereof.
3. The method of one of claims 1 or 2, wherein the compound is:
or a pharmaceutically acceptable salt thereof.
4. A method according to any one of claims 1 to 3, wherein the pharmaceutically acceptable salt is selected from the group consisting of: hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucarate, gluconate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate.
5. The method of any one of claims 1 to 4, wherein the pharmaceutically acceptable salt is fumarate.
6. The method of any one of claims 1 to 5, wherein the compound is:
7. The method of claim 1, wherein the compound is a compound of formula IA or a pharmaceutically acceptable salt thereof.
8. The method of one of claims 1 or 7, wherein R is 2A Is an optionally substituted piperidinyl group.
9. The method according to claim 1, 7 or 8,wherein said R is 2A Selected from the group consisting of:
10. the method of any one of claims 1, 7, 8 or 9, wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
11. A method of treating dry age related macular degeneration (AMD), the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound selected from the group consisting of:
12. a method of treating dry age related macular degeneration, the method comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a compound of any one of claims 1-11 and a pharmaceutically acceptable excipient.
13. A method of treating dry age related macular degeneration, the method comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
14. The method of claim 13, wherein the pharmaceutically acceptable salt is selected from the group consisting of: hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucarate, gluconate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate.
15. The method of claim 13, wherein the pharmaceutically acceptable salt is fumarate.
16. The method of claim 15, wherein the compound is:
pharmaceutically acceptable salts thereof.
17. Selected from the group consisting ofThe manufacture of a compound for use in the treatment of dry senile yellowUse of a medicament for the treatment of plaque.
18. Comprises a member selected from the group consisting of
Use of a composition of a compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient in the manufacture of a medicament for the treatment of dry age-related macular degeneration.
19. The use of a compound or composition according to one of claims 17 or 18, wherein the compound is a pharmaceutically acceptable salt thereof.
20. The use of any one of claims 17 to 19, wherein the pharmaceutically acceptable salt is selected from the group consisting of: hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucarate, gluconate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate.
21. The use of claim 20, wherein the pharmaceutically acceptable salt is fumarate.
22. Use according to one of claims 17 or 18, wherein the compound is:
23. use according to one of claims 17 or 18, wherein the compound is:
24. use according to one of claims 17 or 18, wherein the compound is:
25. The use of claims 1 to 24, wherein the compound is administered orally.
CN202180091728.8A 2020-12-11 2021-12-10 Composition for treating dry age-related macular degeneration (AMD) Pending CN116867488A (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US202063124695P 2020-12-11 2020-12-11
US63/124,695 2020-12-11
PCT/US2021/062850 WO2022125925A1 (en) 2020-12-11 2021-12-10 Compositions for treating dry age-related macular degeneration (amd)

Publications (1)

Publication Number Publication Date
CN116867488A true CN116867488A (en) 2023-10-10

Family

ID=81974688

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202180091728.8A Pending CN116867488A (en) 2020-12-11 2021-12-10 Composition for treating dry age-related macular degeneration (AMD)

Country Status (10)

Country Link
US (1) US20240009168A1 (en)
EP (1) EP4259129A1 (en)
JP (1) JP2023553414A (en)
KR (1) KR20230118158A (en)
CN (1) CN116867488A (en)
AU (1) AU2021396380A1 (en)
CA (1) CA3200346A1 (en)
IL (1) IL303592A (en)
MX (1) MX2023006677A (en)
WO (1) WO2022125925A1 (en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR102331422B1 (en) 2014-01-31 2021-11-25 카그니션 테라퓨틱스, 인코퍼레이티드 Isoindoline compositions and methods for treating neurodegenerative disease
JP7218306B2 (en) 2017-05-15 2023-02-06 コグニション セラピューティクス インク． Compositions for treating neurodegenerative diseases
ES2969373A1 (en) 2022-10-14 2024-05-17 Igen Biolab Group Ag COMPOSITION OBTAINED FROM LYSATES OF PROBIOTIC MICROORGANISMS FOR USE IN THE TREATMENT AND/OR PREVENTION OF DEGENERATIVE EYE DISEASES

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050020483A1 (en) * 2003-06-12 2005-01-27 Donna Oksenberg Sigma ligands for neuronal regeneration and functional recovery
US7829562B2 (en) * 2003-06-12 2010-11-09 M's Science Corporation Sigma ligands for neuronal regeneration and functional recovery
US20110269779A1 (en) * 2008-11-18 2011-11-03 Intellikine, Inc. Methods and compositions for treatment of ophthalmic conditions
KR102331422B1 (en) * 2014-01-31 2021-11-25 카그니션 테라퓨틱스, 인코퍼레이티드 Isoindoline compositions and methods for treating neurodegenerative disease
JP7218306B2 (en) * 2017-05-15 2023-02-06 コグニション セラピューティクス インク． Compositions for treating neurodegenerative diseases

Also Published As

Publication number Publication date
KR20230118158A (en) 2023-08-10
IL303592A (en) 2023-08-01
MX2023006677A (en) 2023-06-27
JP2023553414A (en) 2023-12-21
WO2022125925A1 (en) 2022-06-16
CA3200346A1 (en) 2022-06-16
AU2021396380A1 (en) 2023-06-22
US20240009168A1 (en) 2024-01-11
EP4259129A1 (en) 2023-10-18

Similar Documents

Publication Publication Date Title
CN116867488A (en) Composition for treating dry age-related macular degeneration (AMD)
US10987400B2 (en) Methods for the treatment of glaucoma and age-related macular degeneration by a peptide D-TRP-AIB
CN110869011B (en) Composition for treating neurodegenerative diseases
US9694010B2 (en) Therapeutic formulation and methods of treatment
EP3756665A1 (en) Interval therapy for the treatment of eye diseases
AU2013291970B2 (en) Baclofen and acamprosate based therapy of Macular Degeneration disorders
KR20230159546A (en) Compositions and methods for treating neurological disorders
JPWO2006132205A1 (en) Radical scavenger and active oxygen scavenger
Jo et al. Activation of Lysosomal Function Ameliorates Amyloid-β-Induced Tight Junction Disruption in the Retinal Pigment Epithelium
KR20110126132A (en) Preventive or therapeutic agents for optic nerve disorders comprising 4,6-dichloro-1h-indole-2-carboxylic acid derivatives or salts thereof as active ingredients

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination